Glycobtology vol. 3 no. 2 pp. 97-130, 1993

SPECIAL INVITED REVIEW

Biological roles of oligosaccharides: all of the theories are correct

Ajit Varki1

Glycobiology Program, UCSD Cancer Center, and Division of Cellularand Molecular Medicine, University of California, San Diego, La Jolla,CA 92093, USA

'Correspondence to: University of California, San Diego, Cancer Center,0063, 9500 GOman Drive, La Jolla, CA 92093, USA

Many different theories have been advanced concerning thebiological roles of the oligosaccharide units of individualclasses of glycoconjugates. Analysis of the evidence indicatesthat while all of these theories are correct, exceptions toeach can also be found. The biological roles of oligo-saccharides appear to span the spectrum from those that aretrivial, to those that are crucial for the development,growth, function or survival of an organism. Some generalprinciples emerge. First, it is difficult to predict a priori thefunctions a given oligosaccharide on a given glycoconjugatemight be mediating, or their relative importance to theorganism. Second, the same oligosaccharide sequence maymediate different functions at different locations within thesame organism, or at different times In its ontogeny or lifecycle. Third, the more specific and crucial biological rolesof oligosaccharides are often mediated by unusual oligo-saccharide sequences, unusual presentations of common-ter-minal sequences, or by further modifications of the sugarsthemselves. However, such oligosaccharide sequences arealso more likely to be targets for recognition by pathogenictoxins and microorganisms. As such, they are subject tomore intra- and inter-species variation because of ongoinghost-pathogen interactions during evolution. In the finalanalysis, the only common features of the varied functionsof oligosaccharides are that they either mediate 'specificrecognition' events or that they provide 'modulation' ofbiological processes. In so doing, they generate much of thefunctional diversity required for the development anddifferentiation of complex organisms, and for their inter-actions with other organisms in the environment.

Key words: biological roles/glycoconjugates/oligosaccharides

Introduction

The ability to accurately sequence the oligosaccharide units ofglycoconjugates has revealed a remarkable complexity anddiversity of these molecules (1-18). However, despite someobservations suggesting important biological roles for thesesugar chains, a single common theory has not emerged toexplain this diversity. As recently as 1988, it was stated thatwhile '. . . the functions of DNA and proteins are generallyknown . . . it is much less clear what carbohydrates do' (12).A variety of theories have been advanced regarding the bio-logical roles of the oligosaccharides, and have been presented

© Oxford University Press

in a number of monographs (1-18) and review articles(19-148). These include a purely structural role, an aid in theconformation and stability of proteins, the provision of targetstructures for microorganisms, toxins and antibodies, the mask-ing of such target structures, control of the half-life of proteinsand cells, the modulation of protein functions, and the provisionof ligands for specific binding events mediating proteintargeting, cell—matrix interactions or cell—cell interactions.Most of these discussions have focused either on one specifictype of glycoconjugate (e.g. glycoprotein, proteoglycan orglycolipid) or on one specific theory of function. In thisoverview, an attempt is made to consider together all of thesetheories regarding all of the major types of glycoconjugates.Although the emphasis of diis review is somewhat biasedtowards the glycoprotein oligosaccharides of higher animalcells, the principles that emerge appear to be generallyapplicable to glycoconjugates in all types of organisms.

Because of the broad and diverse nature of the subjectsdiscussed here, a comprehensive bibliography has not beenpresented. In general, the original references are from the last15 years, with a very limited representation of earlier citations.For detailed discussions of the classic and original literature onsome of these matters, the interested reader is referred to thelist of monographs (1-18) and reviews (19-148) provided.

The difficulty in predicting specific rules foroligosaccharide functions: N- and 0-linked sugar chainsas examples

Of all of the different types of glycosylation, the //-asparagine-linked sugar chains are the easiest to manipulate in experimentalsystems. Feasible approaches include the enzymatic or chem-ical removal of completed sugar chains, prevention of initialglycosylation, alteration of oligosaccharide processing, elimin-ation of specific glycosylation sites, and the study of naturalvariants and genetic mutants in glycosylation. Such approacheshave been used extensively to explore the biological roles ofthese sugar chains on a variety of glycoproteins (reviewed in 5,8, 9, 12, 15-17, 20-36, 107-115, 126-131). A summary ofmany such studies is reported in Table I and a shorter list ofsimilar experiments for O-linked oligosaccharides is presentedin Table II. It can be seen that the consequences of altering thesetypes of glycosylation range from being essentially undetect-able, to the complete loss of particular functions, or even lossof the entire protein itself. Even within a given group ofproteins (e.g. cell surface receptors or enzymes), the effects ofaltering glycosylation are highly variable and quite unpredict-able. Furthermore, the same modification in glycosylation canhave a dramatically opposite effect on in vivo function versusthat observed for in vitro function (for example, see the studieson erythropoietin and the gonadotrophic hormones referred toin Table I). These facts underscore a basic principle about thebiological roles of oligosaccharides: they appear to range from

97

A.VarW

TaHe L Effects of altered W-linked oligosaccharides on the biosynthesis, transport and functions of glycoproteins

Protein Effect of lack/alteration of oligosaccharides Examples

Enzymes

Most lysosomal enzymes*-1'-'-'1

Lysosomal 0-glucosidase1

Lipoprotein lipasecj

Yeast acid phosphatase*^

HMG-CoA reductase

Lecithin:cholesterol acyltransferase'

Hepatic lipase11

Arylsulphatase A"

Yeast carboxypeptidase Y1

Propapain11

a,-Antitrypsind

Mucor renin expressed in yeasf1

Purified lysosomal alpha-L-fucosidase*

Ecto 5'-nudeotidaseb-c

Pancreatic ribonuclease B "

UDP-glucuronosyltransferases*

Testicular hyaluronidase*

Hormones/cytokincs/gruwth factors

Glycoprotein hormones (HCG, LH,

TSH, prolactin)*J'-'-<u

Granulocyte/maCTophagecolony-stimulating factor

Erythropoietirr"-11-*

IgE binding factors*1

Interieuldn-4"

Vascular eadothelial growth factor11

Yeast MFal precursor11

Nerve growth factor*

Scatter factor*

Interferon-gamma*

Viral glycoproteins

HTV virus glycoprotein (GP120)*-b-cji

Some viral coat proteins*-^

Some (not all) viral coat proteinsb'cj)

Plasma proteins/coagulation factors

Immunoglobulin D*

ImmimoglobuUns*ub-c-d-t

Loss of targeting signal for delivery of enzymes to lysosomes

Complete deglycosylation causes complete loss of activity

Core glycosylation required for secretion and activity. Processing of oligosaccharides not

important for either

Loss of activity and conformation. Increased susceptibility to denaturation and proteolysis

>90% decrease in ictivity (direct or indirect effect?)

Reduction in catalytic activity without change in K^

Reduced secretion, normal catalytic activity

Variable loss of marmose-6-phosphate-dependem trafficking

Reduced transport rate, especially at higher temperatures. No change in sorting, stability oractivity

Af-Glycosylation of Pro-region required for transport and secretion

Altered CD spectrum and folding. Aggregation

Decreased secretion and decreased activity

No effect on activity or conformation. Shift of pH optimum, decreased stability in acid and heat

No change in subcellular distribution, or GPI-anchor formation

Folding kinetics unchanged, increased susceptibility to proteases

No change in catalytic activity or substrate preference

No change in enzymatic activity. Improved recognition by antibodies

Complex effects. Altered combining of a- and /3-subunits. In some cases, agonist convertedinto antagonist by loss of glycosylatioa. Altered glycosylation causes changes in specificity,affinity, and intracellolar signalling in vitro. Effects on in vivo action are different, because ofaltered clearance

Graded increase in receptor binding and activity with decreased glycosylation. However, increasedanrigemciry and rapid clearance of unglycosylated form

Complex effects. Failure of secretion, decreased stability, and decreased biological activity ifmultiple glycosylation sites are eliminated. Desialylation and/or less branched oligosaccharides giveincreased activity in vitro, but decreased activity in vivo

IgE potentiating factor converted into IgE suppressive factor?

Increase in activity with decrease in glycosylation

Markedly decreased rate and efficiency of secretion. No loss of binding or of activity in increasing

vascular permeability

Delayed transit through the secretory pathway

Natural glycosylated variant still has biological activity

No change in secretion or activity

No change in antiviral activity or target cell specificity

Prevention of glycosylation or prevention of glucose removal results in markedly lowered fusionactivity and decreased infectivity

Variable alterations in antigenicity; increased reactivity with polydonal antisera upon removalOf rhflin*

Complex and variable effects. Complete loss of glycosylation can result in misfolding, retention inthe ER, proteolytic degradation and loss of virion production. Alteration of individual sites showsvarying effects on cell surface expression. Alteration in late processing has little effect onexpression or virion production.

(107-111)

(149)

(150-152)

(153,154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(21,165-167)

(168)

(169)

(126, 170-194)

(195-198)

(129,199-208)

(209-211)

(212)

(213, 214)

(215)

(216)

(217)

(218)

(219-227)

(228-233)

(234-242)

043)Removal causes loss of binding by IgD receptors . .

Complex effects. Altered secretion (variable). Alteration of several secondary effector functions of (34, 244-254)the Fc region. Agalactosyl IgG is associated with granutomatous diseases. Variable region glyco-sylation can enhance antigen binding

98

Biological roles of oltgosaccharides

Table I. continued

Protein Effect of lack/alteration of oligosaccharides Examples

Tissue-type plasminogen activator*-<fc

Haptoglobin"

Antithrombin HI,—natural variant withdecreased carbohydrate

Protein C1

(different sites gave different effects)

Plasminogende

/K-Glycoprotein*

Pro-uroJanasec

Cl inhibitor Tae

Von WUlebrand factor1

FibrinogenMe

Galactoglycoprotein"

Corticosteroid-binding globulinbc

C5a (des-Arg form)1'Complement subcomponent CslAmyloid peptide precursor11

Thyroxine-binding globulin1

Androgen-binding protein''Folate-binding protein11

Protein S (Heerlen polymorphism)'

Increased enzymatic activity and/or lysine binding of certain glycoforms. Glycosylation alters con- (24, 255-261)version to two-chain form

Lost of ability to form a complex with haemoglobin (262)

Increased antithrombin activity. Enhanced heparin binding(?) (263, 264)

No effect on gamma-carboxylation. Improved anticoagulant (increase in K^, decrease in K,). (265)Increase in rate of activation by thrombin/thrombomodulin complex (decrease in K^)

Variations in glycosylation or sialylation associated with differences in cell-surface binding, (266—268)circulatory half-time and fibrinolytic activity

Altered re-folding (269)

Recombinant or mutated enzyme without glycosylation at Asn-302 is two-fold more efficient in (270)activating plasmin

Additional glycosylation site causes dysfunction and disease (271)Variable effects on muftimeric structure and altered function. Increased susceptibility to proteases (272—275)Altered polymerization/aggregation. Sialic acids are low-affinity calcium-binding sites that can (276-280)influence fibrin assemblyEnzymatic removal of - 9 6 % of the carbohydrate caused large changes in CD spectra with (281)increase in the magnitude of the molar ellipticity and amount of /3-tums, and a reduction inrandom coilsAcquisition of binding activity requires glycosylation (282)Removal of oligosaccharide greatly enhances activity (283)No loss of ability to form the functional Cl complex (284)Glycosylation improves tiypsin inhibition by Kunitz-type domain (285)Decreased stability. Small change in affinity for thyroxine and immunoreactivity (286, 287)Decreased secretion. No change in androgen binding (288)Initial glycosylation required for acquisition of binding function (289)Loss of glycosylation site causes no change in protein C binding (290)

Matrix proteins

Fibronectin*-b

Collagen IV 7S tetramerization domainBone and platelet osteonectin°

Membrane proteins/receptors

EGF receptor1'-0

Insulin and insulin-like growth factor-Ireceptorsc-d

Bask fibroblast growth factor receptor"Somatostatin receptor in rat brain andAfT-20 cells'Intercellular adhesion molecule I(ICAM-I)d

Fibronectin receptor (otj/3, integrin)c

Lymphocyte CD2"1

C3h/C4b receptor1*CR2/Epstein—Barr vims receptorb

MHC Class II molecules'1

LuU up in receptor1^Organic cation transporter ofopossum lbdneyb"c

Glucose transporters*-'1

GM-CSF receptor"Erythrocyte band 3 protein1

Erythrocyte CD59 complementinhibitor1^0-2 Adrenergk receptors*-11

Thrombm receptor^gp80 glycoprotein of MDCK cells1"Transferrin receptor expressed invarious cell types'1

Increased susceptibility to proteases (21, 291)Modelling predicts that oligosaccharides are critical in assembly (292)Differences in glycosylation alter collagen-binding properties (293)

Glycosylation-dependent acquisition of ligand-binding capacity. Thereafter, oligosaccharides not (115, 294)required for bindingLoss of binding with complete deglycosylation only. Partial changes in binding affinity/specificity (295—299)with altered glycosylation. Some studies show loss of tyrosine kinase activityLoss of binding of bFGF (300)Sialic acids on the /V-linked oligosaccharides are required for maintenance of the high-affinity (301)binding stateGlycosylation at a single site affects binding to Mac-1, but not to LFA-1 (302)

Normal biosynthesis and expression. Loss of ligand binding (?) (303, 304)Single glycosylation site required for binding of CD2 to CD58 on another cell. Postulated that (305)glycosylation is required for anhiiiTing domain 1, which is involved in adhesionDecreased surface expression, increased turnover. No change C3 binding (306)Decreased surface expression. Increased turnover (307)Variable loss of antigen-presenting function. No loss of peptide-binding function of purified protein (308, 309)Loss of surface expression. No change in ligand-binding capacity (310)Increase in X , without affecting Vwmx of transport (311)

Increase in Km for glucose. Partial or complete loss of activity (312—314)Expression of cr-chain abolished. /3-chain expression normal (315)Increased aggregation. No change in CD spectra, proteolytic susceptibility or anion transport (316)activityNo change in ability to bind CD8/CD9. Loss ( - 9 0 % ) of inhibitory function (317)

No change in expression of ligand affinity. Uncoupling of adenylate cyclase (318—320)Partial loss of high-affinity binding (321)Loss of apical polarized targeting (322)Decreased dimer expression. Decreased binding affinity in intact cells. Elimination of glycosylation (323—326)sites causes partial ER retention and degradation

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A.Varki

Table I. continued

Protein Effect of lack/alteration of oligosaccharides Examples

Nicotinic acetylcholine receptor0

VIP receptor*Membrane Class I MHC proteinVasopressin receptor of LLC-PK1cells*0

Muscarinic acetylcholine receptord

Low-density lipoprotcin receptor1''0

Interferoo-gimma receptorbc

Asialoglycoprotein receptor*-b

46 kDa mannose-6-pbosphate receptor"1

Nucleoside transporter(s) of L1210cells'"CD4 proteinboji

Thyrotrophin receptord

POGF receptor0

Miscellaneous

Jack bean concanavalin Ad-C

Cobra venom factor*Gastric mucinb

Lactotransfemn*Rat intrinsic factor0

ThyroglobuUn*-1'Spinach chloroplast coupling factor*Many secreted animal proteins0

Plant glycoproteins secreted bysycamore cells in culture*1

Decreased expression (increased degradation?), no change in binding affinity (327)No change in expression. Decreased binding affinity (328)Increased lateral mobility in the membrane (329)

Inhibition of biosynthesis and internalization (330)Decreased expression with some mutants. Small change in binding affinity. No change in turnover (331)

or functional responseNo change in expression or in recycling; - 5 0 % decrease in ligand binding capacity. (332)Redistribution between intrtcdlular and surface locationsNormal expression. Loss of ligand binding in the intact cell. However, the purified form is active (333, 334)No change in expression, binding or turnover (335)Glycosylation required for stability of die high-affinity binding state, but not for binding itself, nor (336)for intracellular stabilityNo effect on synthesis or expression. Transport partially affected (337)

Loss of one glycosylation site tolerated. Loss of both sites results in ER retention and degradation (338, 339)Expression unchanged. Elimination of certain sites causes loss of binding (340)Glycosylation not required for acquisition of ligand-binding capacity (341)

^-Linked oligosaccharide keeps the precursor in an inactive form, until it is deglycosylated during (342, 343)

later processingComplete deglycosylation abolishes complement activation (344)Loss of covalent oUgomerization (345)Loss of iron-binding activity (346)Normal secretion and cobalamin binding. Increased sensitivity to proteases (important for normal (347)function in die gut)Altered rootoyrosine-iodotyrosine interactions and immunoreactivity (348, 349)ATPase activity intact. Photophosphorylation activity tost (350)Prevention of glucose removal slows secretion, while blocking of late processing accelerates (351-355)secretion in many grycoproteinsPrevention of glycoiylalion causes marked decrease in secretion, whereaj altered processing has (356)little effect

Note: unless otherwise stated, the proteins are of mammalian origin."Enzymatic or chemical removal of AMinked oligosaccharides.•"Prevention of //-linked glycosylation by tunicamycin (can have pleiotropic effects on other proteins in die same cell).'//-Linked gfycosylation processing inhibitor(s) (can have pleiotropic effects on other proteins in the same cell).''Genetically engineered change in glycosylation.'Natural genetic variant or defect

trivial to crucial, depending on the glycoconjugate, the oligo-saccharide structure, the biological context and the questionbeing asked.

Can one make any sense out of these diverse and confusingfindings? Most prior attempts to approach this issue havefocused on either a single type of glycosylation or on a singletheory of their function. In the following pages, an attempt ismade to undertake a global overview of most of the known factsconcerning the biological roles of oligosaccharides of majorclasses of glycoconjugates in eukaryotic cells, and to synthesizesome general principles for understanding them. Much of theactual data is presented in table form and is necessarilysimplified and/or incomplete. For more details, the interestedreader is referred to the original literature cited in these tables,and to the monographs and reviews mentioned earlier.

'Structural', 'protective' and 'stabilizing' roles ofoligosaccharides

There is little doubt that some oligosaccharides, such as thoseof the proteoglycans and the collagens, are important in the

100

physical maintenance of tissue structure, integrity and porosity(see Table HI). It is also clear that the 'coating' of oligo-saccharides on many glycoproteins can serve to protect thepolypeptide chain from recognition by proteases or antibodies(see Tables I, n and HI) and that the coating of glycoconjugatescovering a whole cell can present a 'glycocalyx' of substantialproportions. Another well-accepted function of the oligo-saccharide units of glycoproteins is that they are involved in theinitiation of correct polypeptide folding in the rough endo-plasmic reticulum (ER), and in the subsequent maintenance ofprotein solubility and conformation (see examples in Tables Iand II). Thus, many proteins that are incorrectly glycosylatedfail to fold properly and/or fail to exit the ER, and are conse-quently degraded. On the other hand, there are many examplesof proteins for which the prevention or alteration of glycosyl-ation has little apparent consequence to their synthesis, folding,or delivery to a final location (see Tables I and IT). Likewise,there are examples wherein removal of the oligosaccharidesfrom a mature protein does not drastically alter sensitivity toproteolysis or immune recognition, nor their functions. Theseapparently contradictory observations exemplify a recurringtheme: that while supporting evidence can be found for many

Biological roles of oligosaccharides

Tabte II. Effects of altered 0-linked oligosaccharides on the biosynthesis, structure, transport and functions of glycoproteins

Protein Effect of lack/alteration of oligosaccharides Examples

GM-CSF1

Tracheal mucin glycoproteins*

Submaxillary gland mucin (molecularmodelling studies)

Intestinal brush border lactose-phtorizin hydrolase (LPHf

Arctic fish antifreeze glycoprotein*

Aspergillus niger glucoamylase*

Erythropoietinc

Glycophorin A1-"1

CD13 (aminopeptidase N)c

LDL receptor1

ApoCIP

/S-HCG1

Single O-linked chain protects against polymerization, denaturation, and loss of certain activities (357)

Removal of sugar chains causes loss of water solubility, requires chaotropic agents or detergents for (358)effective solubilization

Native and asialo-mucin are found to be highly extended random coils. Removal of the carbohydrate (359)side chains causes collapse to chain with dimension] typical of denatured globular proteins

Natural variant glycoform without O-glycosylation has identical K^ value but a 4-fold higher Vtmx (360)

O-Linked oligosaccharides required for freezing-point depression (361)

Partial deglycosylation decreases thermal stability (362)

No effect of elimination on biosynthesis or biological activity. Small effect on secretion rate (?) (199, 205)

Polymorphic changes in amino acids surrounding three O-linked sites give rise to the MN blood (363, 364)group antigens. The intact, unmodified oligosaccharides are required for full antigenicity

Natural variation in the extent of O-glycosylation. Arui CD-13 antibodies do not recognize all (365)

the forms

Multiple O-linked oligosaccharides: some are required for stable expression on the cell surface, but (366—369)not required for LDL binding

No effect on biosynthesis, secretion or lipoprotein particle formation (370)

No change in assembly or secretion, hormonal activity or immunoreactivity (371, 372)

Note: unless otherwise stated, the proteins are of mammalian origin.•Enzymatic or chemical removal of O-linked oligosaccharides.•"Prevention of O-linked gfycosylation by competitive inhibitors (can have pleiotropic effects on other proteins in the same cell).'Genetically engineered change in O-glycosylation.dNatural genetic variant or defect.

Table HI. Cell surface and matrix structure: examples of the 'structural', 'organizational' and 'barrier' functions

Oligosaccharide sequences Interaction with Examples of biological effects Examples

Heparan sulphate chains ofproteoglycans

Chondroitin/dermatan sulphatechains of proteoglycans

Chondroitin sulphate and keratansulphate chains

Dermatan sulphate chain of humanblood protein pre-alpha inhibitor

Siabc acid and sulphate esters onglycoproteins

Qycolipids on epithelial cells

Polylactosamine chains and/or 0-GaIof laminin oligosaccharides

Polylactosamine chains of lamininoligosaccharides

Gtycopbospholipid anchors of somemembrane proteins, //-linked oligo-saccharides of MHC class I proteins

Gastric mucus (major component isgastric mucin, a glycoprotein withmany O-linked sialylated andsulphated chains)

Fibronectin, laminin, collagen, etc.

Extracellular fibronectin

Multiple components of cartilage

Covalent cross-linking to heavychain via esterification

Other negatively charged residues

Other components of apicalmembranes, e.g. GPI anchoredproteins

Bound by 0-galactoside-sperific14 or 35 kDa lectins

Bound by 65 kDa elastin receptorin a /?-galactoside-specific manner?

Other membrane proteins?

Water, ions and ?sdf-ajsociatkm

Organization of basement membrane and extracellular (53, 54, 58, 61,matrix. Filtering function of renal glomerulus. Cell 66, 69, 373-3T7)adhesion to matrix

Deposition of fibronectin in the matrix: ?contact (57, 378-381)inhibition of cell growth

Organization and tensile strength of cartilage (53, 61, 70)

A novel mechanism for cross-linking of two peptide (382)subunits of a protein

Determinant of net negative charge of cell surfaces (7, 40, 383, 384)and proteins: modulates cell-cell interactions andviscosity of secretions

High local concentration on outer leaflet facing the (48, 79, 385-388)lumen of organs: protective or barrier function?

Organization of matrix assembly? e.g. 14 kDa lectin (94, 96, 98, 105,inriiKrs toss of cell-substratum adhesion in developing 106, 389-392)myoblasts during differentiation and fusion intomyofibres

Organization of matrix elastin deposition? (393, 394)

Translational diffusion rates of proteins in the (329, 395)membrane altered markedly

HC1, secreted by gastric glands, traverses the mucus (396)layer without acidifying it because of 'viscousfingering'. HC1 in the lumen (pH 2) cannot diffuseback to the epithelium because of the high viscosity ofgastric mucus gel. Prevents the stomach from digest-ing itself

101

A.Varki

theories regarding oligosaccharide function, exceptions to eachcan equally well be observed.

In general, the development of these 'structural', 'protective'and 'stabilizing' functions during evolution should not haverequired the enormous complexities of structure that are foundin naturally occurring oligosaccharide units. In keeping withthis, inhibitors that only affect the later processing steps ofoligosaccharide biosynthesis generally do not interfere withthese types of functions. In these situations then, the oligo-saccharides are analogous to the 'axle grease' of an automobile.While its absence would markedly affect the ability of the entirevehicle to function, the fine details of the composition of thegrease should not be critical to the turning of the axle. Thus,while these roles of oligosaccharides are vital to the basicstructure and function of the organism, they cannot explain theextensive structural diversity seen in nature.

The 'organizational' and 'barrier' functions

The extracellular matrix consists of a variety of glyco-conjugates, each of which have been shown to have bindingsites for various types of sugar chains, e.g. the heparin-bindingdomains of fibronectin and collagen. Recently, the role of sucholigosaccharide-binding domains in the organization of thematrix has been clearly demonstrated in vitro (see Table HI).Thus, for example, the chondroitin sulphate chain of theproteoglycan decorin is required for the organization offibronectin in the extracellular matrix of Chinese hamster ovary(CHO) cells, which in turn dictates the phenotype of the cellsin culture. In another case, the /3-galactoside-binding function

' of a soluble lectin appears to be involved in the organization ofelastin in the extracellular matrix. Similar functions have beenproposed for the interaction between the polylactosamine chainsof laminin oligosaccharides and certain j3-galactoside-bindinglectins. As shown in the other examples in Table m, oligo-saccharides may also serve to create charge effects and domainsin membranes.

Oligosaccharides as specific receptors for noxious agents:the 'traitorous' functions

It is abundantly clear that certain oligosaccharides can act ashighly specific receptors for a variety of viruses, bacteria andparasites (see Table IV). They are also receptors for many plantand bacterial toxins, and serve as antigens for autoimmuneand alloimmune reactions. In most of these instances, there isexquisite specificity for the sequence of the oligosaccharideinvolved. Thus, for example, the influenza viral haemagglu-tinins specifically recognize the type of sialic acid, its modifi-cations and its linkage to the underlying sugar chain, whilecholera toxin binds with great specificity to GM] gangliosideand not to related structures. Likewise, incompletely synthe-sized (or partially degraded) oligosaccharides such as the Tnantigen can behave as autoantigens in man. There is little doubtabout the extreme specificity of this group of 'functions' ofoligosaccharides (see Table IV). In fact, this specificity hasbeen used to great advantage by scientists investigating theexpression of these sugar chains. However, to the organism thatsynthesized such oligosaccharides, there is little value inproviding such 'traitorous' signposts to aid the access of

102

pathogenic microorganisms or to permit damaging autoimmunereactions.

Oligosaccharide sequences that protect frommicroorganisms and antibodies: the 'masking' and'decoy' functions

Just as certain oligosaccharides act as 'traitorous' signposts formicrobial and immune attack, others can serve to abrogate thesedetrimental reactions (see Table V). In these cases, the additionof specific monosaccharides or modifications masks thesequences recognized by microorganisms, toxins or auto-immune antibodies. Thus, for example, the addition of a singleC*-acetylester to the 9-position of terminal sialic acid residuesabrogates binding of the highly pathogenic influenza A viruses,and the extension of the oligosaccharide chain of GM! wouldprevent binding of cholera toxin. Likewise, the addition ofgalactose and sialic acid to the Tn antigen would abolish itsautoimmune reactivity.

Oligosaccharide sequences on soluble glycoconjugates suchas the mucins can also act as 'decoys' for microorganisms andparasites. Thus, pathogenic organisms attempting to gain accessto mucosal membranes might first encounter their cognateoligosaccharide ligands attached to soluble mucins. Upon bind-ing to these sequences, they could then be swept away by ciliaryaction, leaving me mucosal cells untouched. In these cases, thehost may successfully turn the specificity of the pathogenreceptor to its own advantage.

Oligosaccharides as specific receptors for 'symbiotic'functions

The possible evolutionary interplay between the 'traitorous' and'masking' functions of oligosaccharides is discussed below. Incontrast to these functions of sugar chains, there are some casesin which symbiotic relationships of animals with microorgan-isms appear to be aided by interactions involving specific oligo-saccharides. Thus, certain commensal gut bacteria in animalsand some root nodule-forming bacteria in plants appear tomediate their binding to host cell surfaces via specific sugarsequences, hi these cases, inter-species recognition via oligo-saccharides serves a function useful to both organisms in-volved. It is possible that such interactions are much morecommon and that they have not been carefully sought after.

Effects of oligosaccharides on the biological functions ofproteins: 'on—off and 'riming' functions

There are several examples in which glycosylation can sub-stantially modulate the interaction of peptides with their cognateligands or receptors (see Tables I and VI). Some cell surfacereceptors for growth factors appear to acquire their bindingfunctions in a glycosylation-dependent manner. Thus, the ac-quisition of function of a newly synthesized receptor may bedelayed until it is well on its way to the cell surface. This mightlimit unwanted early interactions with a growth factor synthe-sized in the same cell. Glycosylation of a ligand can alsopotentially mediate such an 'on—off or 'switching' effect.When the hormone human /3 chorionic gonadotrophin (/3-HCG)is deglycosylated, it still binds to its receptor with similar

Biological roles of oligosaccharides

Table IV. Oligosaccharides as specific receptors for noxious agents, antigens for autoimmune responses, or as facilitators of infectious and malignant disease: the'traitorous' functions

Oligosaccharide sequences Recognition by Biological effect* Examples

Terminal sialic acids

Terminal sialic acids

Specific gangliosides on cell surfaces

Specific oligosaccharide sequences ofglycolipids and glycoproteins onmucosal surfaces

Cell surface heparan sulphate chains

Traces of CMP-sialic acid ('serumresistance factor') found in blood

//-Linked oligosaccharides on gastricparietal ceQ proteins

Erythrocyte and platelet glyco-conjugates, e.g. polylactosaminechains on red blood cells ( T antigen)

Incomplete oligosaccharide structuresfrom infectious agents or

Siarylated, fucosylatedlactosaminogrycans on leukocytes

Highly branched and sialylatedAMinked oligosaccharides

Sialylated, fucosylatedlactosaminoglycans on tumour cells

Sialic acids and sialyloligosaccharideson many microbial surfaces

Neural glycosphingolipids

Receptors for a variety of vimshaemagglutinins. Recognition is affected bylinkage and/or substitutions of the sialic

acids

Trypanosoma cruzi trans-sialidase (has bothneuraminidase and sialyltransferase activity)

Receptors for several bacterial toxins e.g.Vibrio cholerae B subunits binds GM1

gangltoskie

Fimbrial proteins of pathogenic orcommensal bacteria; binding receptors ofcertain mycoplasma, chlamydiae, protozoaand fungi

Receptor for herpes simplex virus

?Surface transferase on pathogenic Neisseria

gononhoeae

Required for reactivity of someautoantibodies in autoimmune gastritis andpernicious anaemia

Antigens for spontaneously appearing 'coldagglutinins' and other autoimmuneantibodies

Natural or induced antibodies against theincomplete structures, e.g. Tn antigen

Ligandi for selectin molecules onendothelial cells. System can work 'toowell' under certains conditions of post-ischaemk reperfusion or inflammatinn

Expressed in increased amounts ontransformed cells

Ligands for selectin molecules onendothelial cells

Blocks generation and reactivity of manyantimicrobial antibodies, and facilitatesbinding of complement regulatory protein H

Naturally occurring monoclonal or poly-clonal antibodies

First step in infectious process of viruses. (73, 76, 397-422)Consequences range from lethal disease tomild self-limited infection

Parasite utilizes host sialic acids and (423-430)transfers them to its own surface, blockinganrJgenicity and complement activation

Cell binding and delivery of toxic subunits(e.g. A-subunit of Vibrio cholerae)

First step in infectious process ofpathogenic organisms. Also helps tomaintain localization of normal 'commensal'organisms?

Initiates infection

Sialic acid is transferred to bacterial

(95, 140, 141431-442)

(95, 140-144443-472)

(71, 473)

(474-477)surface, blocking anrJgenicity andcomplement activation

Antibodies associated closely with mucosalatrophy, parietal cell loss—likely to be in-volved in patbogenesis

Autoimmurje destruction of cells, e.g.autoimmune haemolytic anaemia

?Autoimmune damage to cells and organs.Also beneficial because of anti-tumoureffects?

Toxic or inflammatory injury to tissuesmediated by leukocytes exiting the blood-stream in excess

metastatictumorigenicity ""capability of tumour cells?

Enhances metastatic capability of tumourcells via selectin-mediated binding?

Protects microorganism from host antibodiesand alternate pathway of complement

Peripheral neuropathy (in some cases, it isnot clear if the antibody is the cause orconsequence of the disease)

(478)

(123, 479-485)

(486—490)

(83, 84, 86-93,491-495)

(121, 496—502)

(503—505)

(506-511)

(512—521)

affinity, but fails to transmit a signal via stimulation of adenyl-ate cyclase. Thus, an agonist is converted into an antagonist; theprecise mechanism of this effect remains unknown.

In most cases, such effects of glycosylation are not all ornone, but are partial, or relative. In these 'tuning' functions, thebiological activity of many glycosylated growth factors orhormones appears to be modulated over a significant range bythe presence and extent of glycosylation. For example, thecytokine granulocyte/macrophage colony-stimulating factor(GM-CSF) is known to be most active in the unnaturalnon-glycosylated form derived from recombinant technology.However, naturally occurring preparations of GM-CSF containa range of 'glycoforms', each of which shows substantialdifferences in binding affinity and signal transduction (see

Tables I and VI). Another excellent example of this 'tuning'function is seen in the addition of polysialic acid to the neuralcell adhesion molecule (N-CAM), which normally mediateshomophilic binding with identical molecules on other cells (seeTable XI). In the embryonic form, the oligosaccharides of thisprotein carry extended highly anionic chains of sialic acids thatmarkedly reduce its capacity for homophilic binding. Duringdevelopment, the length of these polysialic acid molecules isaltered, such that in the adult state they are much shorter. Thus,the adult N-CAM is capable of more effective homophilicbinding, presumably because there is no longer a need for asmuch plasticity in the nervous system.

In other cases, the function of proteins can be 'tuned' not byoligosaccharides on the receptors or ligands themselves, but by

103

A.Varid

Table V. Oligosaccharide sequences that

Oligosaccharide sequences

9-OAcetyiation

9-O-Acetylatkm4-O-Acetylation

Terminal sialk acids oo glycoproteinsand cell surfaces

Terminal sialk: acids cm 0-Iinkedoligosaccharides

0-Gal residues

Cell surface heparan sulphate

Schistosoma mansoni miracidaoligosaccharide

Heterogeneous oligosaccharides foundon secreted mucins and in milk

protect from microorganisms and immune

Masks recognition of

Terminal siaiic acids

Terminal siaiic acids

0-GaI and/3-GalNAc residues

Core O-linked oligosaccharides (T andTn antigens)

/J-GkNAc residues

Underlying 'activators'?

Underlying antigenic structures of theSchistosoma

Gut epithelial surface membraneoligosaccharides

reactions: the 'masking' functions

Masks recognition by

Influenza A and B viruses (generatesrecognition by other viruses)

Bacterial and viral sialidases

Asialoglycoprotein receptorMacrophage Gal/GalNAc lectin

Natural antibodies to T and Tn antigens

Chicken hepatic lectin

Alternate pathway of complementactivation

The parasite, by the phagocytic cells ofthe invertebrate (snail) host

By various microbial pathogens. Solublemolecules act as inhibitors or 'decoys'

Examples

(73, 74, 76, 403, 404)

(73, 74, 76, 77,522-528)

(116, 120,529)

(486^190)

(116, 530)

(531-535)

(536)

(41, 537)

those on other neighbouring structures. An excellent exampleof this is seen in the modulation of growth factor receptors bygangliosides (see Table VI). The gangliosides are discrete andseparate entities from the receptor proteins. However, it hasbeen well demonstrated that the precise type of ganglioside thatis present in a membrane can have a substantial effect on thetyrosine phosphorylation activity of the epidermal growth factor(EGF) receptor and the insulin receptor. While the precisemechanism of these effects is uncertain and some conflictingdata have been published, it is clear that the specific oligo-saccharide sequence of the ganglioside is required, rather thansimply its net charge or size. Likewise, the polysialic acids ofembryonic N-CAM have been shown to substantially blunt thebinding of apposing cells via other unrelated receptor-ligandpairs, simply by physically expanding the space between cells.An extreme example of a 'tuning' effect of an oligosaccharideon a separate protein is that in which the heparin moleculemodulates the action of the natural anticoagulant antithrombinHI (see Table XI). In this case, the binding of highly specificheparin sequence to antithrombin m converts a very weakantithrombin into a potent anticoagulant. Such heparin se-quences are presumed to have a significant anu'-thrombogenicrole on the surface of endothelial cells that are in contact withthe blood stream.

Since these 'tuning' effects of oligosaccharides are usuallypartial and are rarely absolute, a sceptic might raise questionsabout their importance. However, when taken together, suchpartial effects could have a dramatic effect on the finalbiological outcome. Consider two different cell types that havethe same number and types of growth factor receptors, and thatare presented with the identical concentrations of the samegrowth factors. If the signal delivered to a cell was based onlyon the primary receptor—ligand interactions, there should beno difference in response between these two cells. However, ifdifferences existed in the glycosylation state of the ligands,receptors or membrane gangliosides, each could have a signif-icant positive or negative quantitative effect on the final signalsdelivered to the cell. Furthermore, glycosaminoglycan chainson the surface and in the matrix surrounding the cells could alsomodulate the action of each growth factor differently. Takentogether, the combined effects on the different receptor-ligand-

104

generated signals would be quite different for the two differentcells. These differences would be further amplified by the factthat the intracellular signalling mechanisms of many receptorsshow significant overlap and cross-talk. Thus, the final effectsof the same ligands at the same concentrations on the twodifferent cells in question could be dramatically different. Thus,glycosylation can be a general mechanism for generatingimportant functional diversity, while utilizing a limited set ofreceptor-ligand interactions.

As with most other functions of the oligosaccharides dis-cussed so far, clear exceptions can be encountered. There arereceptors whose ligand binding is not acquired in a glycosyl-ation-dependent manner, and there are ligands whose bindingand action is affected very little by the precise type of glyco-sylation found on itself or on its cognate receptor (see Table I).Once again, it is not possible to make a generalized theorybased on the specific instances studied.

The 'sink' or 'depot' function of oligosaccharides

Another recently appreciated function of oligosaccharidesappears to be that of acting as a protective storage depot forcertain biologically important molecules (see Table VII). It haslong been known that a variety of growth factors could bepurified by affinity chromatography on immobilized glycos-aminoglycan chains such as heparin. It now appears that thespecific growth factors may bind tightly and specifically tocertain glycosaminoglycan chains in vivo. This serves tolocalize the growth factors in question to the extracellularmatrix surrounding the cells that need to be stimulated, andprevents diffusion of the factors to distal sites. There is alsoevidence that such a 'sink' can protect the growth factors fromnon-specific proteolysis, thus prolonging their active lives. Asimilar role may be played by the glycosaminoglycan chainsfound in secretory granules that appear to bind and protectprotein contents after secretion, and to modulate their subse-quent functions. As indicated in Table VII, there are otherclassic examples where oligosaccharides may act as 'sinks' or'depots' for a variety of biological important molecules, rang-ing from water to complement regulatory proteins.

Biological rotes of oligosaccharides

Table VI. Effects of oligosaccharktes on the biological functions of proteins: 'on-off and 'tuning' functions

Peptide(s) Type of oligosaccharides Biological effect(s) Examples

Glycoprotein hormones, e.g. /3-HCG W-Linked oligosaccharides on the hormones

Haematopoietic growth factors(e.g. GM-CSF and erythropoietin)

Interleukin-1 and interieukin-2

Various growth factors andcytokines, e.g. FGFs, GM-CSF,IL-3, Pleiotrophin, IL-7 and thymkstroma-derived T-cell growth factor

Several proteases, proteaseactivators and protease inhibitors(other than antithrombin i n andheparin co-factor n, see Table XH)

Jack bean concanavalin A (Con A)

Some growth factor receptonb>c-<l

Some growth factor receptors (EGFreceptor, insulin receptor)

Certain intncellular proteinand pbosphodiesterases

Cell surface integrins

Unknown

Unknown

Unknown

Transcription factors, cytosolicproteins and RNA polymerase

Glycopbospholipid anchors ofmembrane proteins

W-Linked oligosaccharides on the factors

Binding to high-mannose-typeoligosaccharides on other molecules

Binding to heparan sulphate chains (eitherfree, or in the proteogiycan form)

Interaction with heparin/heparan sulphatechains

AMinked high-mannose-typeoligosaccharide on the newly synthesizedlectin

//-linked gtycosylation-dependantactivation: completion of disulphide bondsand native conformation requires partialprocessing of oligosaccharide (?)

Up- or down-regulation of tyrosinephosphorytation by specific gangliosidespresent in the same plasma membrane.Effects on growth control?

Modulation of phosphorylatkm by specificgangliosides. In some cases, specificphenotypk responses are seen in targetcells

G m and Gpj gangliosides

Specific types of gangliosides, particularlythose with more sialic acids

Neolacto- and GM gangliosides.Granulocytic or monocytic differentiation ofmyetoid precursors correlates with theirexpression

Different gangliosides added exogenously toneural cells in culture or administered towhole animals

O-LJnked GlcNAc residues at multiple sites

Other membrane proteins? Signallingsystems?

Required for signal transduction: removal (126, 127, 170-174,results in conversion to an antagonist. Role 176, 178, 538)in normal biology not fully defined

Binding affinities and biological activities (129, 195-197,change substantially with differing degrees 199-205, 208, 538)of glycosylation

Generates a surface membrane-bound form, (539—543)of uncertain function. The cognateoligosaccharides show immunosuppressiveactions in vitro

Controlled release from matrix. Negative (57, 60, 62-64, 72,and positive regulation of growth-promoting 544-565)effects? In some cases, heparan sulphatechains are required for high-affinity bindingof factors by their receptors

Varying degrees of positive or negative (69, 566-573)modulation of activities

Keeps the precursor form inactive, until it (342, 343)is deghycosylated during later processing

Prevents premature association of growth (115, 294-298)factor made in the same ceil with itscognate receptor?

Permits modulation of the function of (47, 49, 574-582)receptors without altering their number oraffinity for die ligand. Role in normalbiology not yet well defined

Modulation of signal transduction. Role in (46, 583—597)normal biology not yet well defined.Topological incongruity unresolved

Calcium-dependent association appears to (598-603)modulate adhesive function. Role in normalbiology not well defined

Suppressive effects on cell proliferation in (51, 604-617)the immune response. May be important inthe immunosuppressive effect! of cancers.Role in normal biology not well defined

Exogenous addition of these gangliosides (52, 618-620)triggers die appropriate differentiationresponse. Role in normal biology not welldefined

Neurotrophic effects, promoting (45, 50, 621-647)differentiation, potentiating healing,protecting from neurotoxic agents andpromoting calcium fluxes. Role in normalbiology not well defined

Indirect evidence suggests that expression (145, 648, 649)may be rapidly regulated inversely withphosphorylation at the same rites —amechanism for modulation of activities?

T-cell activation via different surface (650-652)proteins requires GPl-anchon

105

A.Varki

Table VII. Maintaining local concentrations of specific molecules: examples of the 'sink' or 'depot' functions

Otigosaccharide sequences Molecules bound and locally concentrated Proposed biological effects Examples

Matrix and/or basementmembrane heparan sulphatechains

Cell surface and matrix heparansulphate chains

Secretory granule proteoglycans

Chondroitin sulphate chain ofmacrophage colony stimulatingfactor (M-CSF)

Plasma membrane gangliosides

Cell surface sialic acids

Sialylated A*-linked oligo-mrcharidrs in sea urchin

Sialic acid residues of fibrinogen

Cell surface sialic acids oncardiac cells

Surface sialic acids onsynaptosomes

Sialic acids, uronic acids andsulphate esters on manygrycoproteins and proteoglycans

Pig gastric mucus (majorcomponent it gastric mucin, aglycoprotcin with many 0-linkedsialylated and sulphated chains)

FGFs, GM-CSF and other cytokines in cellbasement membranes or intercellular matrix

Superoxide dismutase

Binding to other components of the granule,e.g. enzymes

Specific and selective binding ofoligosaccharide to matrix Type V collagen

Calcium

Facilitates high local binding and retention ofcomplement regulatory protein H on cellsurfaces

Calcium

Calcium ('low-affinity' binding site)

Calcium

Sodium?

Water

Water and bicarbonate ions

Maintains local concentration and availability (57, 60, 64, 72,of growth factor to the relevant cells. 544—560, 565,Protection of factors from proteolysis. Release 653-655)upon injury to endothelium stimulatesangiogenesis?

Maintenance of local concentration of the (656)enzyme in tissues?

Permits packaging of materials into storage (657-661)granules? Protects, localizes and modifiesactivity of bound molecules after secretion?

Maintains high local concentration of this (662)form of M-CSF in bone marrow matrix andodier sites of action?

Local increases in Ca2 + concentration, affect- (663)ing receptor recognition processes?

Prevents activation of the alternate pathway of (510, 523, 532,complement on homologous surfaces (requires 664-674)unmodified sialic acid side chain)

Facilitates Ca2 + sequestration for deposition (675)into the CaCQ, skeleton

At physiological Ca1* concentrations, (277)facilitate proper fibrin polymerization

Removal of sialic acid markedly alters (676—678)calcium currents into the cardiac cells

Removal of sialic acid markedly changes (679)kinetics of Na+-dependent uptake of thegamma-aminobutyric acid and D-aspartate

Help to create gel states of mucins and extra- ( 1 - 3 , 41, 54, 61,cellular matrix 65, 396)

Bicarbonate ions secreted by the gastric (396)epithelium are trapped in the mucus gel,establishing a gradient from pH 1-2 at thelumen to pH 6—7 at the cell surface

'Intracellular trafficking' functions of oligosaccharides

The best understood example of such functions is the role ofmannose-6-phosphate residues in targeting newly synthesizedlysosomal enzymes to their final destination in the lysosomes(see Table VJLLL). In this case, the human disease states in whichphosphorylation is deficient (I-cell disease and pseudo-Hurlerpolydystrophy) are characterized by a failure of lysosomalenzyme targeting in several cell types. This provides conclusiveevidence for the importance of the oligosaccharide modificationin mediating this important pathway. However, it is notable thateven this elegantly precise function of oligosaccharides appearsto have its exceptions: mannose phosphate is not absolutelyrequired for the trafficking of lysosomal enzymes in somelower eukaryotes, nor is it essential in certain cell types inmammals. As indicated in Table Vin, many other endocyticreceptors that recognize specific carbohydrate sequences havebeen described. However their role, if any, in intracellulartrafficking (i.e. during the biosynthesis of glycoconjugates)has yet to be defined.

106

The role of oligosaccharides in regulating the 'clearance'or turnover' of proteins and whole cells: 'intercellulartrafficking'

The effects of glycosylation on the stability of proteins toproteolysis has already been mentioned, and can presumablyaffect meir turnover and half-life in the single cell. In the intactanimal, recognition of oligosaccharide sequences by certainreceptors can result in removal of the glycoconjugate or eventhe whole cell from the circulation. There have been severalwell-documented examples of the action of such 'intercellulartrafficking' receptors (see Table VOT). Many of these inter-actions are highly specific for the oligosaccharide sequencesrecognized by the receptors, suggesting that their biologicalroles are equally specific. In several cases, rational meorieshave been put forward to explain the functions of theseclearance pathways (see Table VIE). However, to date therehave been very few naturally occurring mutants in thesereceptors described in an intact animal. This makes it difficultto obtain definitive proof of such functions.

Biological roles of oligosaccbarides

Table VIII. Intra- and inter-cellular trafficking of proteins: 'targeting' and 'clearance' functions

Oligosaccharide sequences recognized Lectin Proposed role in protein trafficking Examples

Phospborylated high-mannose-type

oligosaccharides on lysosomal

enzymes and other proteins

Exposed terminal /3-Gal residues on

mammalian plasma proteins

Exposed terminal 0-GlcNAc residueson avian plasma proteins

Terminal 4-O-sulphated 0-GalNAcresidues on glycoprotein hormones

Mannose-rich oligosaccharides ofendogenous and exogenous origin

Gal/GalN Ac-terminatedoligosaccbarides of endogenous andexogenous origin

//-Linked higb-mannose-typeoligosaccharides of endogenous andexogenous origin

Cation-independent M6P receptorCation-dependent M6P receptor

Asialogrycoprotein receptor

Chicken hepatic lectin

Specific receptor in the non-parenchymalliver cells

Macrophage Man/Fuc receptor

Macrophage Gal/GalNAc receptor

Circulating 'core-specific' lectin

Trafficking of newly synthesized lysosomalenzymes to lysosomes. Salvage of secretedphosphorylated enzymes?

Clearance from circulation: determinant ofhalf-life? Abnormalities in liver diseases,but significance unproven in normal

Clearance from circulation: determinant ofhalf-life?

Rapid clearance from circulation:determinant of short half-life?

Clearance of proteins from circulation?

'lectinophagocytosis' of pathogens?

Clearance of proteins from circulation?

'lectinophagocytosis' of pathogens?

Opsoninization of pathogens, allowingcomplement activation and phagocytosis.Clearance of proteins from circulation?

(107-113, 680-#>6)

(116, 117, 120, 529,697)

(116, 530, 698)

(118,699,700)

(95, 97, 119,701-708)

(709-711)

(97, 119, 712-714)

'Hormonal' actions of oligosaccharides

It is now recognized that free oligosaccharides can themselveshave biological effects in various systems, thus acting likehormones (see Table LX). The best documented examples arethe 'oligosaccharins' of plants, which induce specific responsesin a manner highly dependent on the structure of the sugarchain. Likewise, free high-mannose chains can have strongimmunosuppressive effects in in vitro mammalian systems in amanner dependent upon the specific structure of the sugarchain. It is also likely that free heparin fragments released bycertain cell types have effects on other cell types, acting perhapsvia binding and intemalization. However, in most of these casesthe putative receptors for these molecules have not beenidentified, and the mechanisms by which they work remainuncertain. Many other less well defined oligosaccharides orglycopeptides with proposed biological effects are known, andare listed in Table DC.

Role of oligosaccharides in 'cell-cell and celkmatrixrecognition'

Since all cells are covered with a dense coating of sugars, it haslong been predicted that oligosaccharides must be criticaldeterminants of 'cell-cell interactions'. In actual fact, there arerelatively few examples in which such functions have beenclearly defined (see Table X). Perhaps the best-documentedexample is that of the selectin family of receptor proteinsthat mediate the adhesion of leukocytes to endotheUal cells(L-selectin), the recognition of leukocytes by stimulated orwounded endothelium (E-selectin), and the interactions ofactivated platelets or endothelium with leukocytes (P-selectin).In each case, the minimal carbohydrate ligands involved inrecognition appear to be sialylated fucosylated sugar chains,such as sialyl Lewis" and sialyl Lewis*. However, biologicallyrelevant recognition may require specific glycoconjugates that'present' multiple copies of such oligosaccharides in a spec-ialized fashion, i.e. in a proper spacing on the linear poly-

peptide chain, or in the proper three-dimensional context Inthis regard, we have recently suggested that oligosaccharidesthat are very closely spaced together on the polypeptide mightbe packed tightly together, generating a 'clustered saccharidepatch' for specific recognition. This would allow the generationof uncommon recognition markers utilizing common oligo-saccharides. Alternatively, specific modifications of the oligo-saccharides (e.g. sulphation) might be creating unique bindingsites. There is also now substantial evidence that the binding ofsperm to eggs involves the Olinked oligosaccharides on thezona pellucida glycoprotein ZP3, possibly by interacting witha surface jS-galactosyltransferase. Other clear examples ofcell-cell binding involving specific carbohydrates includeCDw44, macrophage sialoadhesin and the B-cell lectin CD220(see Table X). In many of these cases, rational theories can beconstructed to explain the role of these cell—cell interactions.However, with the exception of the selectins, the specificbiological significance of these recognition events has not beenconclusively demonstrated in the intact animal.

A variation on this theme has been the proposal that carbo-hydrate—carbohydrate interactions may play a specific role incell-cell interactions and adhesion. Several examples of suchinteractions have been presented and appear to show specificityfor the structural details of oligosaccharides involved (see TableX). For example, there is provocative evidence that duringmurine embryogenesis, the stage-specific embryonic antigen(SSEA) which appears at the 16-cell stage is important in thecompaction of the embryo, due to an Le*—Le* interaction. Theaffinities of such interactions can be measured with somedifficulty and do not appear to be very strong. However, if themolecules in question are present in high copy number on thecell surface (e.g. glycolipids), the summing of a large numberof relatively low-affinity interactions could result in a sub-stantially higher avidity, sufficient for biological relevance.Such a 'velcro' effect may well be sufficient to mediatebiologically relevant recognition.

In many of these cell-cell interactions, protein—protein bind-ing phenomena clearly also play critical roles, e.g. the LFA-I/

107

A.Varid

Table IX. Biologically active oligosaccharkles and glycopeptides: 'hormonal' actions

CHigosaccharide sequences recognized Target tissues or cells/cognate receptor Reported biological effects Examples

Specific /3-glucan oligosaccharides ofPhytophxhora fungal cell walls

Polygalacturonic oligosaccharkles ofplant cell walls

Exopolysaccharide of Rhizobium

species. Specific sulpbated, acylated or

fucosylated sequences

Oligosaccharides derived from

sycamore cells

Free heparin/heparan chains fromadjacent cells, e.g. smooth muscle cellsand endothelial cells

Glucosamine-containingoligosaccharide(s)—derived fromglycosylphospharJdyl inositol?

Sialylated fucosylated glycopqxidefrom brain cells

A glycopeptide from malignant tumoureffusions. An acceptor forgalactosyhransferase

A sialogtycopeptide circulating inpatients with sepsis or trauma

Free sialylated N-Hrikedoligosaccharides released from troutegg glycoproteins during oogenesis

Various plantsUnknown receptor

Tomato and potatoUnknown receptor

Alfalfa or soybean root cellsUnknown receptor

Tissue culture 'callus' of tobacco cells orduckweed cells. Unknown receptor

Unknown receptor in nucleus? Eventually

works via c-fos and c-myc in endothelial

cells

Various mammalian cell types

Unknown receptors)

Various animal cell typesReceptor of 150 kDa?

Various tumour cell typesOligosaccharide required for binding:receptor unknown

Unknown

Unknown

Elichor of production of phytoalexins(plant antibiotics against fungi)

Bicitor of production of phytoalexins.Induces phosphorylation of specificmembrane proteins and morphologicalchanges in cultured H« IW»

Elicits root nodulatkm in host: determinantof symbiotic relationship betweenRhizobium and plants

Selective induction of vegetative buddingor floral growth: hypothesized to modulateorgan development in the intact plant

Inhibition of cell growth

Proposed second messengers for some

(136, 137, 715-717)

(137, 718)

(138, 139, 719-724)

(725)

(60, 726-736)

Interleukin-2, NGF, and inailm-fTwyfinfr^signal transduction events

Growth inhibition of a variety of celltypes

Growth inhibition, antitumour effects

Induces endogenous proteoiysis in ratmuscle, simflnr to that occurring inpatients

Unknown. Large quantities suggest aspecific function

(80, 737-749)

(750-752)

(753, 754)

(755)

(756-759)

Table X. Lectin—carbohydrate and carbohydrate-carbohydrate interactions: examples of 'cell:cell and cdhmatrix recognition'

Lectin Oligosaccharide sequences recognized Proposed biological functions Examples

E-Selectin (ELAM-1)

P-Selectin (GMP-140/PADGEM/CD62)

L-Selectin (LAM-1, MEL-14 antigen,LHR)

CD44 (Hermes, Pgp-1)

CD220 lectin of B-lymphocytes

Macrophage Gal/GalNAc receptor

Macrophage sialic acid-specific receptor

Kupffer cell-specific Gal/Fuc receptor

Sialylated fucosylated polylactosamino-glycans on unknown leukocytegrycoconjugates

Sialylited fucosylated polylactosamino-glycans (on a specific myeloid £lyco-protein?) (sulphated ligands as well?)

Sialylated, fucosylated, sulpbated oligo-saccharides (on specific glycoproteins?)(other sulphated ligands as well?)

Hyalurorric acid

a2-6-linked sialic acids on lactosamineunits of specific glycoproteins, e.g. CD45

Terminal 0-Gal or /3-GalNAc residues on

blood cells or pathogens

Sialic acids on surface grycoconjugates,

in the sequence Sia a 2-3Gal 0 l-3GalNAc

?Specific oligosaccharide structures in liver

matrix

Primary adhesion of granulocytes, (760—771)monocytes and certain lymphocytes toacutely or chronically inflamedendothelium

Primary adhesion of granulocytes, mono- (763, 766, 768,cytes and certain lymphocytes to activated 770, 772—780)platelets or endothelium

Adhesion of granulocytes to inflamed (770, 771,endothelium and of naive lymphocytes to 781—787)endothelium of high-endothelial venules: adeterminant of lymphocyte trafficking

Adhesion of many cell types to endothelial (788-795)cells and matrix. Additional determinant oflymphocyte trafficking

Early step in interactions of B-cells with (796-800)activated T<dls or activated B-cells.Cross-Unking of CD457

Clearance from circulation: determinant of (709—711)half-life?? Phagocytosij of pathogens?

Interaction of bone marrow macrophages (801-804)with haematopoietic precursors and lymphnode macrophages with lymphocytes?

??Mechanism of localization and retention (805-808)of Kupffer cells in liver

108

Biological roles of oligosaccharides

Table X. continued

Lectin Oligosaccharide sequences recognized Proposed biological function* Examples

Surface /51-4 galactosyltransferase

Unknown, on mammalian sperm

Cell surface/soluble /S-galactoside-t>indinglectins in a variety of cell types

Cerebellar soluble lectin

Extracellular matrix proteins (e.g.laminin, fibronectin, thrombospondin)

Several extracellular matrix proteins (e.g.laminin, thrombospondin) membranereceptors (e.g. P-selectin) and solubleproteins

Macrophage migration inhibitory factor

Unknown

Unknown receptor in epithelium ofsandfly midgut

Gal-specific lectin of Bradyrhizobiumjaponkum

Unknown receptor on Capnocytophagaochracea

GlcNAc-terminating oligosaccharides ontarget cells? Transfcrase acts as a lectin?

a-Linked Gal residues on O-linkedoligosaccharides of egg protein ZP3

/3-Galactoskle ind/or polylactosarrrineresidues on other cells or in the matrix

31 kDa endogenous glycoprotein ligand?

Binding to beparan sulphate chains on cellsurface proteoglycans

Binding to 3-O-sulphatedgalactosylceramide (sulphatide)

Specific cell surface ganglioside

//-Linked glvcans, in some cases carryingpolylactosamines

Lipophosphoglycan of Leiihmania only innon-infective stage promastigotes

Unknown ligand on plant cells

Specific hexasaccharide repeat from cellwall of Streptococcus sanguis

Sperm—egg receptor function? Inducer of (147, 809—821)acrosome reaction? Role in cell migrationduring development and tissueorganization? Role in neurite extension?Role in tumour metastasis?

Sperm-egg recognition. Inducer of (822-824)acrosome reaction? Competing theory withsurface ^-galactosyltransferase

Implicated in cell-cdl and cell-matrix (94, 96, 104-106,interactions in development and tissue 390, 825—838)organization. Also may serve as receptorsfor certain immunoglobulins. Role intumour metastasis?

Mediates contact guidance of neuron (99, 100,migration by astrccytes? 839-843)

Role is mediating cell adhesion, (376, 844-850)differentiation, spreading or invasion

Role in mediating cell attachment and/or (774, 851—861)differentiation?

Lymphocyte cytokine that modulates (862, 863)macrophage migration into tissues?

Complex literature suggesting roles for (101, 864—868)oligosaccharides in interactions betweenlymphocytes, and between natural killercells and their targets

Allow stage-specific adhesion of non- (869)infective stage promastigotes and selectiverelease of infective stage promastigotes

Facilitates symbiotic interactions? (870, 871)

Co-aggregation of the two bacterial strains (872)is implicated in formation of dental plaque

CARBOHYDRATE 1 CARBOHYDRATE 2

Multimillkm molecular weightaggregation factor (MAF)

Xanthan gum polysaccharide

Hyaluronan

Baaeroides fragilis capsular poly-saccharide A

Lewis1 structure

ganglioside

MAF

Carob gum polysaccharide

Chondrohin sulphate

B.fragilis capsular polysaccharide B

Lewis1 structure

G,3 or Lac-Cer glycolipids (carbo-hydrate-carbohydrate interaction)

Mediates cell-cell recognition in the (873, 874)sponge Microciona proUftra

Intermolecular binding mediates gelation (875)and Tbinding of Xandwmonai bacteria

Specific inter-molecular (876)interaction—significant in matrixorganization? Involvement of protein notruled out

Strong ionic interactions create a complex, (877)aggregated polymer—a virulence factor

?MecSates compaction of the morula-stage (878-880)embryo

?Mediates interaction between different (881-883)cell types

I-CAM interaction in leukocyte—endothelium binding (87).However, these interactions appear to require activation of thecells and do not seem to work well under the shear forcespresent in the flowing bloodstream. Several lines of evidenceindicate that oligosaccharide-protein interactions provide the

initial specificity for the interaction, and the strength andpermanence of the association is then mediated by protein-protein interactions (reviewed in 87-93). This would allow theparsimonious use of a limited set of protein—protein interactionsas a generic glue for a variety of cell—cell interactions, while

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A.Varki

leaving the specificity to the diversity of oligosaccharidestructures.

Such intercellular interactions should be most importantduring embryonic development. The number of genes(50 000—100 000) available in the genome of a mouse cannotpossibly account for the numerous specific steps required forcomplete murine embryogenesis if a different gene wasrequired for a each step. However, a set of glycosyltransferasesexpressed in various combinations could provide a wide varietyof different potential ligands for cell—cell interactions. Thefrequent demonstration of regional, spatial and gradient expres-sion of carbohydrate structures during embryonic developmentstrengthens the notion that such specific interactions are indeedimportant at various steps in development However, proof thatsuch interactions are important requires the availability ofmutants with genetic defects in glycosylation.

Do any general principles emerge?

The discussion so far makes it clear that the oligosaccharideunits of glycoconjugates have many and varied functions. It alsoleads to the conclusion that while all of the theories about theirfunctions appear to be correct, exceptions to each can also befound. A corollary of this conclusion is that it is difficult topredict a priori the functions of a given oligosaccharide on agiven glycoconjugate. Fortunately, some other worthwhileprinciples do emerge from this analysis.

Temporal and spatial differences in the expression ofoHgosaccharides: the same structure can have multipleroles

The expression of specific types of glycosylation on differentgryconjugates in different tissues at different times of develop-ment implies that these structures must have diverse anddifferent roles in the same organism. For example, mannose-6-phosphate-containing oligosaccharides were first describedon lysosomal enzymes and are clearly involved in targetingthem to lysosomes. However, since that time, mannose-6-phos-phate-containing oligosaccharides have been found on a varietyof apparently unrelated proteins, including proliferin (1038),thyroglobulin (947, 948), the EGF receptor (1039) and thetransforming growth factor £ (TGF-0) precursor (895). Whilethe significance of these observations is uncertain, they raisethe possibility that mannose-6-phosphate-containing oligosac-charides have other biological roles. Likewise, the sialylatedfucosylated lactosamines critical for recognition by the selectinsare also found in variety of other tissues, where the selectins areunlikely to be functioning (16, 17). The polysialic acid chainsthat appear to play such an important role in embryonicN-CAM have also been found on proteins as diverse as an eggjelly coat protein and a sodium channel protein (18). Likewise,9-O-acetylation of sialic acids is found on a variety of differentglycoconjugates, in a variety of different tissues at differenttimes in development (7, 74, 76).

Given that oligosaccharides are post-translational modifica-tions, these observations should not be entirely surprising. Onceit is expressed in an organism, the same oligosaccharidemodification could have independently evolved several distinctusages in different tissues and at different times in development.If any one of these functions were vital to the survival of the

organism, then the transferase mediating the expression ofthe oligosaccharide structure would be conserved in evolution,thus perpetuating the less important situations where it wasexpressed as well. It is even conceivable that expression of aparticular structure on a particular glycoconjugate might be ofno positive consequence whatsoever in that particular situation.However, the transferase responsible for this structure mayhave been selected because of its vital contribution to the func-tion of an entirely different glycoconjugate. As long as therewas no strongly negative consequence for the first glyco-conjugate, its expression might persist in that situation and beconsidered 'revenue neutral' for the organism.

Can the interplay between traitorous' and 'masking'functions result in the formation of 'junk'oligosaccharides?

The 9-0-acetylester group that abrogates binding of the highlypathogenic influenza A viruses to sialic acids simultaneouslygenerates a specific binding site for the less pathogenicinfluenza C virus and coronaviruses (see Tables IV and V).Such 0-acetylated acids are frequently found on mucosalsurfaces of mammals Perhaps the mammalian organism firstattempted to mask the sialic acid receptor for the highlypathogenic influenza A virus by adding an O-acetyl group to it.However, subsequent selection could have resulted in theappearance of microorganisms (influenza C and coronaviruses)capable of binding specifically to the 'masking' structure.

Since microorganisms and parasites evolved in parallel withtheir multicellular hosts, they may have had to constantly adaptthemselves to bind to each new 'masking' structure evolved bythe host. In response, the host organism may have found it mostefficient to generate new masking structures, perhaps becausethe existing structure had already evolved a vital functionelsewhere within the organism. Having committed itself to thiscourse of action, the host would then be left with no choice butto keep the underlying 'scaffolding' upon which the latest'mask' was placed. Thus, yet another layer of complexitywould have been added to its oligosaccharides. Such cycles ofinteraction between microorganisms and hosts could explain inpart some of the extremely complex and extended sugar chainsfound on mucosal surfaces and secreted mucins. It also leads tothe possibility that 'junk' oligosaccharides do exist akin to'junk' DNA. While serving a general (and important) functionas a scaffolding, they may have no other specific definable role.

Inter-species variations in glycosylation

The existence of species-specific variations in glycoconjugatestructure indicates that some oligosaccharides do not playfundamental and universal roles in all biological systems. Forexample, the glycolipids of red blood cells from variousmammalian species show striking differences both in theprimary sequence of the glyconjugate and in the type of sialicacid on the acidic glycolipids (see Table XII). Likewise, whenthe ^-linked glycosylation on a conserved protein such asgamma ghitamyl transpeptidase was examined from a variety ofspecies, marked differences were seen in the sequence of thesugar chains (35). Such variations between species in the glyco-sylation of similar proteins or cells imply that these sugar chainscannot be crucial for the basic functions of these proteins orcells. On the other hand, such diversity in glycosylation could

110

Biological rotes of oligosaccharides

Table XI. Unique or unusual types of glycosylation more frequently mediate specific biological roles

Molecules) modified Unusual or unique type of glycosylation Proposed biological role(s) Reviews and examples

Lysosomal enzymes

TGF-/3 precursor

Neural cell adhesion molecule(N-CAM)

Endothdial and mast-cell heparansulphate proteoglycans

Extracellular matrix dermaunsulphate proteoglycans

Cell surface and matrix heparansulphate

Pituitary glycoprotein hormones

Rhizobium polysaccharides

Specific glycoproteins on myeloidand eodothelial cells

A'-Cadherin

T jminir)

Placenta] fibronectin

Endothelial thrombomodulin

Cytosolic parafuscin

Gtngliosides of nervous systemand neural crest cells

Several neural cell adhesionmolecules

Thyroglobulin

Mannose 6-phosphate on high-mannose-typeoligosaccharides

Mannose 6-phosphate ?in high-mannose-type oligosaccharides

Polysialic acid

3-O-sulphation of selected GlcNAc residuesin specific pentasaccharides

4-O-S-GalNAc and 2-0-S-G1A residues inthree sequential disaccharide repeats

2-O-S-IdoA residues within definedsequences

GalNAc 4-SO4 terminating antennae of/V-linked oligosaccharides

Sulphatkm and acylation of /91-4-Unkedgtucosamine residues

Sialylated, fucosylated (and sulphated?)lactosaminoglycans

GalNAc-phosphodiesten on O-linkedoligosaccharides

Polylactosaminogrycans on W-linkedoligosaccharides

Polylactosaminogrycans on AMinkedoligosaccharides

Chondroitiii/dermatan sulphate chainattached to a fraction of the molecules

Glc-P-Man on 0-linked oligosaccharides

O-Acetylation of a terminal a2-8-linkedsialic acid residue on potysialosyl units

HNK-1 epitope/Ll epitope: sulphatedglucuronic acid residues?

0Gal 3-SO4 |3GlcNAc 6-SO4

Mannose 6-pnosphate

Intracellular trafficking of enzymes bybinding to mannose 6-phosphate receptors

Intercellular traffic of precursor to permitactivation in acidic endosomes?

Inhibition of homotypic binding between

N-CAM molecules and general inhibition of

intercellular adhesion involving other

binding systems. Positive effects also?

Antithrombin Hi binding and activation,

resulting in anncoagulabon

Heparin co-factor II binding and activation,resulting in anticoagulation

Required for high-affinity binding of bFGFto its cell surface receptor

Effects upon turnover, plasma half-life andbioactivity of the hormones

Symbiotic host specificity: elidtation of roothair deformation and nodulation

Primary recognition motifs for the selectinfamily of cell adhesion molecules

?Involved in modulating adhesive functionsof the cadherin in neural development

Binding to soluble ^-galactoside-bindinglectins (galaptins): matrix organization?

Decreased binding to gelatin. ?Alteredbinding functions in the placenta

Negative regulation of all of theanticoagulant activities of thrombomodulin

Very rapid changes in phosphorylationaccompanying activation and exocytosil?

Expression is temporally and spatiallyregulated. Abnormalities seen in transgenicmice with decreased O-acetylation in certaintissues

Some evidence for direct involvement incelhcell adhesion

?Role in uptake and/or processing ofthyroglobulin into thyroid hormones

(107-112, 681, 683,884-894)

(895)

(18, 896-907)

(58, 62, 908-913)

(914, 915)

(72, 558)

(118, 130, 699, 700)

(138, 139, 719-724)

(83, 84, 86-93,760-768. 768-771,773, 777, 778,780-785)

(916-921)

(390, 825, 834,922-924)

(925)

(926-930)

(931, 932)

(933-940)

(941-946)

(947-952)

certainly be involved in generating the many obviousdifferences in morphology and function that are observedbetween species. Such differences could also reflect differingselection pressures resulting from different pathogens that infectthe different species.

Intra-species variations in glycosylation

Genetic polymorphisms with no known biological consequenceare quite common in proteins. For example, in Sweden alone,at least nine different albumin variants were found, with acombined prevalence of 1:1700 in the population (1046). Thegenetic polymorphisms in glycosylation diat are recogruzed as'blood-groups' (discovered because of the unnatural practice of

blood transfusion) also have limited consequences for thenormal biology of humans. Similar intra-species polymorph-isms have been observed between the sialic acids on red bloodcells or hepatocytes in different in-bred strains of mice and dogs(see Table XII). It is clear that substantial intra-species poly-morphism in oligosaccharide structure can exist withoutobvious reason. However, these polymorphisms may be of farmore importance in the wild state, where protection againstcertain microorganisms or other noxious agents could prove tobe of survival value to a segment of the population expressinga specific oligosaccharide structure. In some cases, the patho-gens that originally selected for such polymorphisms may havedisappeared from the environment in the very recent evolu-tionary past, leaving behind the unexplained polymorphism.

I l l

A.Varid

Table XII. Genetic defects or polymorphisms in glycosylation are uncommon in higher animals, but have variable consequences

Genetic defect/variation Basic defect in glycosylation Biological consequences) References

Partial or complete deficiency oflysosomal enzyme: UDP-GlcNAcGlcNAc-phospbotransferase

Partial deficiency of UDP-GlcNAc:a-mannoside GlcNAc transferase IIor processing a-mannosidase II

Partial deficiency of xylosylprotein4-0-galactosy Itrans ferase

?Decreased conversion ofGDP-fucose to GDP-mannose(general fucose deficiency)

?Deficiency of PAPS:Lactosaminoglycansulpbotransferase(s)

Defects at multiple steps inassembly of the glycopbospholipid(GPI) anchor precursor (7acquiredgenetic defect in haematopoieticstem cell)

Mosaic deficiency of UDP-' galactose: GalNAc 3-0-

galactosyltransferase affecting asubset of cells (usually acquired)

Galactose-1-phosphateuridyftransferase deficiency

Decreased synthesis of3 '-phospboadenosine5'-phospbosulphate (PAPS)

Hereditary opsonic defect

Partial or complete failure ofphosphorylation of mannose residues onlysosomal enzymes

Incomplete processing of AMinkedoligosaccharides: decreased addition ofpolylactosamine units

Decreased production of glycosaminoglycanchains with core Gal£l-4Xyl linkage

Low levels of GDF-fucose, low levels offucose on all glycoconjugates

Decreased sulphatkm of keratan sulphate incornea (?) and other tissues

Lack of pre-formed donor for GPI-anchonng of pro terns

Decrease in Gal01-3GalNAc of O-Unkedoligosaccharides. Increase in GalNAc-O-Scr(Tn antigen)

Defect primarily affects low molecularweight pools of galactose-rdated molecules.However, some abnormal galactosylation ofcomplex carbohydrates is also noted

Decreased surphation of glycosaminoglycansand abnormalities in proteoglycans

Point mutation in serum mannose-bindingprotein

Partial or complete failure of lysosomalenzyme trafficking in I-cell disease(mucofipidosis 0 ) and Pseudo-Huiierpolydystrophy (MUU)

Hereditary erythrocytic multinuclearity withpositive acidified serum test (HEMPAS),also known as congenital dyserythropoieticanaemia type II

Progeroid syndrome with delayed mentaldevelopment, and multiple connective tissueabnormalities

Leukocyte adhesion deficiency type n. Lowfucose on many glycoconjugates results inlack of ligands for selectins, and poorleukocyte adhesion. Bombay Blood grouptype. Infections, short stature, mentalabnormalities, skeletal defects

Macular corneal dystrophy type I:progressive clouding of the cornea resultingin blindness

Paroxysmal nocturnal haemoglobinuria(PNH): failure of GPI anchoring/secretionof several cell surface proteins on bloodcells —haemofytk *nam\a increasedinfections, progression to malignancy

Potyagglutinability of red cells by allnormal human sera: variable haemolyticunarm is. Can be seen as a precursor toleukaemias

May account for some of the abnormalitiesthat persist when patients are treated withgalactose-free diets

Brachymoiphic mice with skeletalabnormalities (because of partial defect,tissues with the highest sulphaterequirement, e.g. cartilage, are mostaffected)

Heterozygous state causes low opsonizationof pathogens. Increased infections inchildhood

(107-111,953-959)

(131, 960-965)

(966,967)

(968)

(969,970)

(132, 971-978)

(486,979-982)

(983,984)

(985-987)

(988-990)

Terminal sequences, unusual structures and modificationsof oligosaccharides are more likely to mediate specificbiological roles

It is reasonably clear that the biological roles of oligo-saccharides can range from those that are trivial to those thatare critical for the development, growth, function or survival ofan organism. The challenge then is to predict which sugarchains are likely to mediate the more specific or crucialbiological roles. Review of the matter suggests that terminalsugar sequences, unusual structures or modifications of theoligosaccharides are more likely to be involved in such specificroles (see Table XI). For example, the high-mannose oligo-saccharide structures of lysosomal enzymes are identical todiose found on a wide variety of proteins, ranging from theimmunoglobulin IgM in nrmrpmal<: to the lectin soybean

agglutinin in plants. It is reasonable to suggest tiiat such awidely expressed structure is less likely to be involved inmediating specific biological functions. On the other hand, theaddition of phosphomonester residues to one or two of themannose units results in the generation of the highly specificphosphomannosyl recognition marker that dictates traffickingof die enzyme to the lysosome. Likewise, segments of thecommon heparin/heparan disaccharide repeating unit are con-verted into specific ligands for antithrombin HI or basicfibroblast growth factor (bFGF) by a highly ordered series ofepimerizanon and sulphation reactions. Similar, although lessconclusive arguments can be made for other modifications suchas polysialic acids, O-acetylation of sialic acids, polylactos-aminoglycan chain formation and outer chain fucosylation (seeTable XI).

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Biological roles of oligosaccharides

TaHe XH. continued

Genetic defect/variation Basic defect in grycosylation Biological consequences) References

IgG cryoglobulin

Type I procoUagen in i case ofosteogenesis imperfecta

Saposin B in a case of congenitaldeficiency

Haemophilia A variant

Cl inhibitor Ta

Albumin Redhill

Protein S (Heerien polymorphism)

Deficiency of UDP-Gal:3-or-galactosyhxansferase (inhumans, apes and Old Worldmonkeys)

Polymorphic expression of active ornull aDetes for UDP-Gal: H-precursor3-a-galactosyltransferase(B-enzyme) and UDP-GalNAc:H-precursor 3-a-N-acetylgalactos-amim/ltransferase (A enzyme)

Polymorphic expression of Sd*antigen in humans

Polymorphic expression of UDP-Gal: Galorl-4 galactosyltransferases(the P blood group system). Someindividuals lack the enzyme(s)(blood group p)

Primary enzymatic basis not fullydefined

Differing levels of expression ofganglioside biosynthetic enzymes inthe livers of different inbred strainsof mice

AMJnked glycosylabon in first heavy chain

hypervariable region

?New //-linked giycosylation site in

carboxy-terminal peptide

Point mutation eliminates a new AMinkedgiycosylation site

Point mutation creates a new AMinkedgiycosylation site

Additional giycosylation site created bythree-base deletion

New grycosylttion site and altered signalpeptidase cleavage

Loss of giycosylation site

Marked decrease ofGalal-3Gal01-4GlcNAc sequencesterminating glycoprotein and gfycolipidoligosaccharides

Polymorphism expression of A and B andO blood groups structures terminatingglycoprotein and glycolipid oligosaccharides

Poryroorphism in expression ofGalNAcj31-lfNeuAca2-3]Gal0l^GlcNAc

Polymorphism in the expression of P, PIand P* blood group structures terminatingglycoprotein and glycolipid oUgosaccharides

Polymorphic expression of Af-acetyl andA/-grycolyl-neuraminic acid on theerythrocyte gangliosides of dogs and cats

Differences in the overall pattern ofganglioside expression in the liver and otherorgans

Precipitation of immunoglobulin in the cold, (991)leading to vascular problems

Cause of increased fragility of bones? (992)

Unmasking of proteolytic site causes rapid (993)turnover, resulting in deficiency

Decreased function of Factor VIII, leading (994)to bleeding disorder

Type n hereditary angioneurotic edema (271)

No obvious phenotype(?) (995)

No change in protein C binding. (290)

No phenotypeNo obvious abnormality results. (996-999)All humans have a natural antibody (up to1 % of circulating IgG) against Galal-3-Galj31-4GlcNAc sequencesNo obvious abnormality results. Humans 90, 123, 148,have natural antibodies against the Mood 1000-1003)group sequences that they do not express

No obvious abnormality results (1004, 1005)

No obvious abnormality results. Individuals (140, 141, 444-446,with some P blood groups are at greater 449, 450)risk for urinary tract infections with E.colicarrying specific P-fimbriae, became theyexpiets the cognate oligosaccharide ligandon their urothdial surfaces

No grossly obvious consequences in dogs. (1006—1008)Possibly related to the geographicco-migration of dogs with humans, andsubsequent breeding patterns. In cats, thisaccounts for a major blood group system

No grossly obvious consequences (1009-1012)

Note: unless otherwise stated, the defects reported in this table were found in humans.

Unusual oligosaccharides or modifications are also morelikely to arise from interactions with microorganisms andother noxious agents

The constant balance between the 'traitorous' and 'masking'functions of oUgosaccharides has been discussed above (seeTables IV and V). In most cases, it is the terminal or outersugars and their modifications that are involved in these life-and-death interactions. Consequently, while such structuresmay be more involved in specific biological roles within theorganism, they are also most likely to vary as a result ofhost-pathogen interactions. However, the two functions neednot be mutually exclusive. For example, it is possible that whileO-acetylation of sialic acids on mucosal surfaces may play aprotective role in host—microbial interaction, the temporal andspatial gradients of expression of O-acetylation found in the

developing nervous system may play important roles in theprocess of development in the brain. The challenge then is topredict and sort out which of these two completely distinct rolesare to be assigned to a given oligosaccharide structure.

In some cases of sporadic autoimmune reactions to oligo-saccharides, the antigenic structures are normally present inadult tissues (e.g. antibodies against peripheral nerve glyco-lipids seen in some individuals with multiple myeloma).However, there are examples of oligosaccharide structureswhich when expressed postnatally by the organism resultuniversally in an immune response. The best examples inhumans are the conversion of A/-acetylneuraniinic acid toiV-glycolylneuraminic acid (1040, 1041) and the expression ofGalal-3 Gal sequences (see Table XH). In these cases, thestructures are not expressed in normal adults, but can appear in

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A.Varki

disease states such as cancer, resulting in immune reactions dueto newly induced or pre-existing antibodies. In at least one case(N-glycolylneuraminic acid), it is clear that expression actuallydoes occur in the normal fetus, but is then suppressed post-natally in the normal adult. The oligosaccharides in questionevidently must have no normal functions in the adult. However,it is likely that their expression in the fetus is a required eventand is a case of ontogeny recapitulating phytogeny.

Is there a common theme to the varied functions ofoligosaccharides?

We have reviewed the evidence that all of the diverse theoriesregarding the functions of oligosaccharides are correct, but thatexceptions to almost every theory can also be found. In the finalanalysis, the only common feature of all of these functions isthat they either mediate 'specific recognition' events or that theyprovide 'modulation' of biological processes. In so doing, theyhelp to generate the functional diversity that is required for theevolution and development of different types of cells, tissues,organs and species. There is a limited number of genesavailable in the genome for the generation of such diversity.Thus, it should not be surprising that an oligosaccharidestructure resulting from the action of a single gene productcould be utilized to generate a wide variety of functions indifferent tissues at different times in the life cycle of theorganism. However, even complete knowledge about thestructure, biosynthesis and expression of a particular type ofstructure does not necessarily give us clues to its specificfunctions. The challenge before us is to design experiments todifferentiate between the trivial and crucial functions mediatedby a given oligosaccharide.

Approaches to uncovering specific biological roles ofoligosaccharides

Some functions of oligosaccharides are discovered serendipi-tously. In most cases, the investigator who has elucidatedcomplete details of the structure and biosynthesis of a specificoligosaccharide is still left without knowing its functions. If itis possible to make educated guesses about the role of the oligo-saccharide in question, this can sometimes lead to definitiveexperiments. However, conclusive proof of the biological rolesof an oligosaccharide sequence often requires analysis ofmutants that are defective in such a structure. It is thereforeuseful to consider the lessons that have been learned to date bystudying such mutants.

Genetic or acquired defects in glycosylation are easilyobtained in cultured cells, but have somewhat limitedconsequences

The essential pathways of biosynthesis of most of the majorclasses of oligosaccharides have now been worked out andinvolve a large number of gene products, including manyfamilies of glycosyltransferases. Tissue culture cell lines withmutations in a variety of specific steps in the biosynthesis ofN-tiriked oligosaccarides, glycosaminoglycans, O-linked oligo-saccharides and glycophospholipid anchors have been obtained,including some with defects in very early steps in the bio-synthetic pathways (for examples, see 30,71,1043,1044).

Mutants affecting the biosynthesis of dolichol sugars, sugarnucleotides or sugar nucleotide transport into the Golgiapparatus have also been obtained, and have pleiotropic effectson the biosynthesis of multiple types of glycoconjugates in thesame cell. Likewise, cell lines can be grown in the presence ofglobal inhibitors of the biosynthesis and processing of severaltypes of oligosaccharides (for example, see 1042). In most ofthese situations, the abnormalities in glycosylation seem to havelimited consequences to the growth and maintenance of thesetissue culture cell lines. This suggests that many (though not all)aspects of glycosylation are of limited importance in the day-to-day housekeeping functions of the single cell, when it is in aprotected environment, under optimal conditions of growth. Ofnote, however, some of these mutants do show alterations indensity-dependent growth inhibition and others demonstratechanges in tumorigenicity or metastatic behaviour wheninjected into athymic mice (1045). This suggests that many ofthe more specific biological roles of oligosaccharides need to beuncovered by studying mutations in the intact multicellularorganism.

Genetic defects in glycosylation are rare in intactorganisms, but have highly variable consequences

In contrast to the situation in vitro, genetic defects in glyco-sylation are surprisingly rare in intact organisms. There are fewother biochemical pathways in which naturally occurringmutants in mouse and man are so uncommon. In the fewinstances in which glycosylation mutants have been observed inintact complex multicellular organisms, the consequences havebeen highly variable (see Table XII). In humans, the effects ofgenetically altered glycosylation range from severe lethaldiseases such as I-cell disease to apparently unremarkable con-sequences such the ABO blood group polymorphisms.Glycosylation mutants in intact mice are even more uncommon.The rarity of such naturally occurring mutations could beexplained in several ways. It is possible that they do occurfrequently, but have little detectable biological consequence.A more likely possibility is that the great majority of them causelethal aberrations that prevent completion of embryogenesis.A third possibility is that mutations in glycosylation remainundetected because of alternate or 'fail-safe' mechanisms thatensure that vital biological functions are carried out by morethan one pathway. In this regard, it is worth noting that the con-genital absence of a variety of highly conserved proteins inhumans (e.g. glycophorin A, haptoglobin, prekallikrein,myeloperoxidase, coagulation factor XII and high molecularweight kininogen) are also known to have little biological orpathological consequence. Likewise, many 'knockout' experi-ments involving highly conserved proteins such as cellularproto-oncogenes have surprisingly limited consequences in theintact mouse (1047, 1049).

Creating mutants in glycosylation in intact organisms:a challenge for the future

To explore these issues, it appears necessary to create mutantsin glycosylation in intact animals. Several possible approachescould be taken towards this goal. Antibodies or lectins specificfor certain oligosaccharide sequences could be expressed intransgenic animals or injected into specific developing tissues.However, since such molecules are multivalent, they may

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Biological roles of oligosaccharides

TaHe XTJI. Altered oligosaccharides in diseases without • known primary defect in glycosylation

Glycoconjugale{s) affected Change in oligosaccharides Biological effects) References

Plasma fibrinogen in bepatoma and incongenital dysfibrinogenaemias

Plasma membrane and secreted proteinsin cystic fibrosis

CD43 Geukosialin, sialophorin) inWislcott-Aldrich syndrome

Serum IgG immunoglobulin

Several plasma proteins

Dolicbol oligosaccharides

Increased branching or number of AMinkedoligosaccharides and increased sialic acidcontent

Generalized increase in fucosylatkm andsulphalicm

Altered branching of 0-linkedoligosaccharides

Decreased galactosylation of AMinkedoligosaccbarides

Abnormal N-linked glycosylation of someglycoproteins. ?Primary or secondary defectin glycosylation

Altered processing and accumulation ofdolichoi-linked mannosyl-oligosaccharides

Prolonged thrombin time and reptilase time. (278-280)Inhibition of coagulation

TContribute to change in physical properties (1013, 1014)of secreted glycoproteins

Decreased expression (due to altered (1015-1020)glycoiylationT)

A general feature of many chronic (34, 248, 254)granulomatous diseases (rheumatoid arthritis,Crohn's disease, tuberculosis, etc.)

'Carbohydrate deficient glycoprotein (1021-1032)syndrome'. Growth abnormalities,characteristic fat accumulations, abnormaldectrophoretic mobility of certain serumglycoproceim, due to Valtered glycosylation

Neuronal Ceroid-lipofuscinosis. ?Primary or (1033-1036)secondary defect in humans, dogs and sheep

Note: unless otherwise stated, the defects reported in this table were found in humans.

disrupt development or other functions simply by causingunwanted cell-cell adhesion. Alternatively, the molecular clon-ing of glycosyltransferases allows overexpression, or thecreation of 'knockout' mice lacking a specific sugar sequence.If such an intervention blocks early embryogenesis, the con-sequences may not be available for analysis (study of first-generation chimeric animals may give some information ingene-deletion experiments). However, even if live homozygousanimals are observed with overexpression or with genedeletions, care must be taken in interpreting the results. Theconsequences seen could be the result of interference with othercompeting glycosylation pathways, or may be due to non-specific physical effects of grossly altered glycosylation in alltissues of the organism.

An alternate approach makes use of the fact that manymicrobial degradative enzymes are highly specific for certainouter sugar chain sequences. Thus, direct injection of specificendoneuraminidase into developing neural tissues yieldeddramatic phenotypic changes (901, 905), suggesting specificroles for polysialic acids, and injection of heparanase into thedeveloping embryo caused randomization of left-right axisformation (1048). Expression in transgenic mice of a viral sialicacid-specific 9-O-acetylesterase under the control of specificpromoters caused abnormalities either early or late in devel-opment (940). In principle, the latter approach could begeneralized to any situation where a cDNA is available encod-ing a specific oligosaccharide-degrading enzyme. Thus, ratherthan interfering with the basic genetic and cellular machineryresponsible for the synthesis of specific oligosaccharides, onemight eliminate them selectively after normal synthesis byexpression of a degradative enzyme as a cell surface molecule.Specific promoters should limit expression of the enzyme andallow the analysis of tissue-specific functions of oligosac-charides in later stages of development, side-stepping an earlylethal event that could have occurred with a gene 'knockout'experiment. In the short term, such approaches are likely togenerate even more new questions than immediate answers.However, it is much better to have many incomplete clues tothe biological roles of oligosaccharides than to have extensive

and specific structural information only, and no way to pursuetheir relevance.

Future prospects

As recently suggested, modern progress in glycobiology 'hasfinally opened a crack in the door to one of the last greatfrontiers of biochemistry' (36). The future now appears brightfor the understanding of many new biological roles of oligo-saccharides. Until recently, mainstream research was focusedeither on the molecular biology of the single cell, or on thephysiology of whole organs or organisms. In both of thesedisparate areas, the roles of oligosaccharides tend to be lessprominent and can often be ignored or bypassed. However, thefuture of biology and biotechnology now lies in studies ofcell-cell interactions, embryonic development, tissue organiz-ation and morphogenesis, and in the integration of these studieswith the molecular physiology and pharmacology of organs andorganisms. In these arenas, the biological roles of oligo-saccharides seem to be critical and their understanding becomescrucial to further progress.

Acknowledgements

The author thanks George Palade, Hud Freeze, Jeff Esko, Jerry Hart, Jerry Siu,Marilyn Farquhar, Mike Bevilacqua, Nissi Varki, 014 Hindsgaul and StuartKomfeld for helpful comments and discussions. Work in the author's laboratoryhas been generously supported over the years by the National Institutes ofHealth, The American Cancer Society and the Veterans Administration.

Abbreviations

bFGF, basic fibrobtast growth factor, CHO, Chinese hamster ovcry; EGF,epidermal growth factor; ER, endoplasmic rcticulum; GM-CSF, granulocyte/macrophage colony-stimulating factor; HCG, human chorionk gondotrophin;HNK-1/L1, the antigenic ephope recognized by the HNK-1 antibody; I-CAM,intercellular adhesion molecule; LDL, low-density upoprotein; LFA-1,leukocyte function antigen 1; MHC, major histocompatabiliry complex;N-CAM, neural cell adhesion molecule; SSEA, stage-specific embryonicantigen; TGF, transforming growth factor.

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A.Varid

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333. Fucher.T.. Thoma.B.. Scheunch.P. and PfizenmaterJC (1990) Grycosylarion of the humanimerferon-gamma receptor. N-linked carbohydrates coaribote to structural beterogeoeity and arerequired for lifand binding. J. Bid Otm.. 265. 1710-1717.

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364. Prohaskajt.. Kaeroer.T.AJ.. ArmnageXM. and Farrhmayr.H. (1981) Chemical and carbon-13nuclear •^pwir runmnrf studies of the blood group M and N active sialogfycopeptides fromhuman glycophorin A. J. Bid Oum.. 256. 5781-5791

365. O'ConneflJJ., Cerkn.V. and O'ApkxAJ.F. (1991) Variable O-glycosybuion of CD13(smbopepridaie N). J. Bid Ourn.. 266. 4593-4597.

366. Davis.C.G.. EDwnmti.A.. Rimdl.D.W., Sdmeider.WJ.. Komfeld^.. Brown.M.3. andGoldstemJ.L. (1986) Odctioa of clustered 0-imked carfaohydiates docs not t rn** funcDoo oflow density Bpoprotdn receptor u transfected fibrooUja. J. Bid O n . 261. 2828-2838.

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368. Kuwano.M.. Segucbi.T. and OooM. (1991) Grycosylmon mutatiora of serine/rhreomne-linkedrrllriTw fliinftn la low-density lipoCTOtrin rcccpcor*. lnftHp**nnMf rala ot O-ctycosytuiocL/. Cffl ict .98. 131-134.

369. Srgirfri.T.. MerkleJtK.. Oao.M., Kawano.M. and Cumminp.R.D. (1991) The dysfunctionalLOL ruxptu in a monensin-feslsant mutaal of Chinese hamster ovary cells lacks selectedO-Uaked oligosaccharides. ArdL Biodum. BScfhyl.. 284, 245-256.

370. Roghani jk. and Zaonis.V.I. (1988) Mutagenesis of the glycosylation sue of human ApodJL 0-Unked gtycosybnkn b not required for ApoCHI secredoo aad liptd buamg. J. Bid Own, 263.17925-17932.

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376. Carey.OJ.. CmmblingJ}.M., StaUJLC. and EvuaJD.M. (1990) Anociaooo of cell surfacebeparaa sulfate pronogrycans of Schwaan cells wnh extracellular matrbt proteiiis. / Bid Oheai,265, 20627-20633.

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378. Yamagnchi.Y and RuoslahtiX- (1988) Expression of human proteogrycaa ia Chirjese Uamsmovary cells inhibits cdl prolifcnnoa. Heart, 336, 244-246.

379. UBirooJLC.. EskoJ.D., WoomvA.. Johansson^, and HookM. (1980 Adhesion ofgivcosaminoflycan-dcfkient Chinese hamster ovary ceD mutants to flbronecrin snbimta. / CtUBid, 106. 945-952.

380. BldanseuDJ.. UBaroaJL. Rajenberg,L.. Murpny-UllriczuJ.E. and HookX. (1992) Regulaooaof ceU substme adhesion: Effects of smafl |^lac»osan*>oglycan-containiag proteoglycans. y. CMBid. 118. 1523-1531.

381. DdaJ., SkubtxA.P.N., FurcsuL.T.. Warneri.A- aad McCantayJ.B. (1992) Coordmne rolefor ceD sarface cbondroidn sulfate piuieuglycan and o*B\ integral in "~<»^"f mtlauuma ceDadhesion ID flbronecdn. J. CM Bid. 118. 431-444.

382. EaghOdJJ.. Salvesen,G.. HtfoJ.A.. ThogerseaJ.B.. RutbermrdJ. and PtttoJ.V. (1991)Choadroirin 4-sulfate covalenrly cross-Unks rhe chams of tbe human blood protein pre-o-moibaDr.J. Bid OHM.. 266. 747-751.

383. KapseabergJlL.. Sdetona,F.E.M.. KalhnuA.. BojJ.D. and RocarmoadJLC. (1989) Tberesli'mive roW of sialic add in antigen presentation to s subset of buman puipbejal CD4*T lymphocytes the requires araigen-presamng dendritic ceUs. Emr. J. bmamd. 19. 1829-1134.

384. Ardman3.. SJionkJ.Mjk. and Slaunma.D.E. (1992) CD43 iulufnes with T-lymphocyteadhesion. Pwc Ned. Acad. Sri. USA. 19. 5001-5005.

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387. Browu,D.A. and RoatJ.K. (1992) Sorting of GPI-ancbored proteins to gtycoUpid-earicbedmembrane tnrrlmmnn during transport 10 tbe apical cdl surface. CtU, 68. 533-544.

388. Dotti.CG.. PirtDoJLG. and SimoraJC. (1991) Polarized sotting of grypialed proteins tohmpocampal neuions. Naturt, 349, 158-161.

389. Cooper.D.N.W., Masa^.M. and Barondes^.H. (1991) Endogenoas muscle lectln Inhibitsnrrobhtn adhesion to lammin. J. CtO Bid. 115. 1437-1448.

390. Zbou.Q. and C lnfi.R P (1990) The S-type Lecrm from calf bean dssue binds setecttvdy tothe carbuliydiale coaim of lamlnia. Ardu Biodum. Bhfmjs., 281, 27-35.

391. Woo.H.-J.. Lotz.M.M., JuagJ.U. and Mercario^.M. (1991) Carbohydrate-binding proton 35(Mac-2). a lamtma-binding t^f^n forms ftn^t^ml dimcrs using cysteine 186. J. Bid Ottm.,26t>. 11419-18422.

392. RosenbergX. CbcriyUJJ.. UsdbacnerJU. and PObu S. (1991) Mac-2-bindiag gl»i<4)li.ilrlinPutative ugands for a cyttaolic 0-galactoside trctm J. Bid Oitm., 266. 18731-18736.

393. H M O . , Wram,DJ.. Mectam.R.P. and BaroodesJ.H. (1988) The dasnn retepiu. agabcmaide-bindtag protein. Sdna, 239. 1539-1341.

394. McchcnJLP.. WtutebouseX.. Hjy.M.. HineiuA. and Shmr.MJ. (1991) Ugand affmity of die67-kD etafiin/banimn binding protein b modulated by die nrotem's lectln domala: Vbualizatiooof elastin/laminin-feceptor complexes with gold-agged Hgands. J. CtU Bid. 113. 187-194.

395. LemanskyJ'., Fateml^.H., Gorican.B., Meyale^.. RosseroJL and Tanakoff.A-M. (1990)DynamiaandkngevltyofrhegryailipU-aactDrednietnbnmeraT^^ CtU Bid. UO.1525-1531.

396. BbaskarJLR.. OarikJ'.. Tumer3.S.. BradleyJ.D., Bansfljl., StanttyJl.E. and LaMonU.T.(1992) Viscous fmgermg of HO throorh gastric mucin. Namrt, 360. 451—461.

397. Martwen.M.A. and PaulsonJ.C. (1980) Sendai virus adbzes specific rialytoUgosaccbarides ashost cefl iixqum •^trnr^r^n Prx. fad. Aad. Sd. USA, 77. 5693-5697.

398. MarkweUJ>4.A.. Svnmrrholm.L. and PaubonJ-C. (1981) Specific gangftmirtn function as hostceD receptors for Senon rints^Proc Nad. Acad. Set USA. 78. 5406-5410.

399. CarroUXM. and PantaoJ.C.-(4«5) Difreremial infection of receptor-modified bos ceDs byreceptor-specific bfraeuza viruses. Vina Ra-, 3. 165-179.

400. Rogers,G.N.. Dmicts.R-S.. SkrheUJ., WDeyXI.C.. WangJCF.. HlgaJLH. and PauisoaJ.C.(1985) Has-imdiited - ^ ^ - of tofbienza virus receptor variamx Sialic add-alpha 2.6Gau-spedfic doses of Vduck/Ukraine/1/63 revert to sialic acid-*lpha 2JGat-specifk wOdrypetaovo.J. Bid Otm.. 260, 7362-7367.

120

Biological roles or oligosaccharides

401. Suzuki.Y.. Sumb.T.. M n u n p . M . and Mmmnu.M. (I9S5) GangUosides as paramyxovirusietr|j<ui. Structural lequiiemcrfl of sialo-otlfosacchiriacs m imxpms for hrTnaqr"tl"*ring virusof Japan (Sendai yina) and Newcastle disease virus. 7. M a . (Toho). 97. IIS9-1199.

402. Sazub'.Y.. Mimrmp.M. and Mauamoto.M. (I98S) W-AatyincurarriiriyuactnsylcrraTrode.GM3-NeuAc. • new mftnenza A vina rectum wtucb medaaes the admpiioo-fusiop process ofviral iofectioa. Binding specificity of tnftueaza vina "A/Aicm72/68 (H3N2) to uieuibiafic-•nodnedGW wto aWcreffl n»lecuiaT species of sialic add. / Slot Otm.. 260, 1363-1363.

40}. ftoferi.G.N..Herrier.G.. PaulsanJ.C. «nd Heok.H.D. (1986) Influenza C virususei 9-O«xryl-rV-acetytneuraminic add as a high affinity tixqmji determtnanl for ••'• I'nr •• to cells. J. BioLCVrm., 261. 5947-5931.

404 Herrler.G.. Remer.G.. R00.R-. KlenkJl.D. md SctaocrJt (1917) M«xtyl-9^>KXIytacunmnKacid, me receptor determinant for inftuenza C virus, is a differentiation marker on rtnrtrneryrhrccytes. I M Ctan. Hopot StyUr . 361. 431-454.

403. Herrler.G., Ron.R.. Kknk.H.D.. Muller.H.P.. ShukhuA.K. and Schanerjt. (19*5) Tbereceptor-destroying enzyme of influenza C virus b netmnunse-Oacetyttslense. EMBO J.. 4.1503-1306.

406. Wia.H.H.. Rogen.G.N. and PanliociJ.C. (I9S5) Inflaenza virus hunaajJuOuim duTerenmuebcrweeo receptor detenniiiaiia bearing S-tcaj\-, N-grycoryl-. and //.Odueerylnearambnc aods.Wrvbfj, 144. 279-252.

407 Kga.H H. and PaunrjrU.C (1983) Sialytanan of gtycoprotdn ofafosacdarides with fV-acctykA'-gtycoryK and ^-O-ducetylrieimminic acids. J. BioL Cntm., 260. 8S38-8S49.

408. Mochmore.E. and Varta,A. (1987) Inacdvatioo of influenza C essnrase decreases mfectrvirywithout loss of binding, a probe for 9-O-Ketyuued sialic adds. Sdencr, 236. 1293-1295.

409. Prhchrn.TJ. and PaulsonJ.C. (19*9) Basil for the potent tnMbtaon of influenza virus infectionby equine and goinea pig <r,-macrog!obalin. J. SbL Chtm., 264. 9830-9858.

410. Weat.W.. BrownJ.H.. CtusckJ.. PaulsonJ.C. SkeheU-l. and WueyJJ.C. (1988) Smtcmreof tne infhjcoza vims haemaggtnrinm complexed with in itcejjux. stalk add. Naairt, 333,426-431.

411 Wmoogbbyjt.E. and Yoaen,R.H. (199O)SA11 rotaviruao ipccifkalry tahibrtodby aoacetytatdsiabc Kid. J. Infra. Or.. 1(1. 116-119.

412. Hara.T.. Endo.T.. PurukawaJC. KawaldtaJH. and Kobata,A. (1989) Ehckladon of the pheoo-typk change on tne surface of Had-I cell, a mtant cell Utie of m o i FM3A carcinoma cellsselected by rtsisailce to Newcastle disease virus infecdoa. /. Biodam. (Tokyo}, 106. 236-247.

413. Pml.fLW.. Choi.A.H.C. and Lcc.P.W.K. (1989) Tbt o-aaomeric form of italic acid is theminimal receptor determinant rrrngniTrri by reovirus. Viroioa, 172. 382-3S5.

414. FukudomcX. Yoshfc.O. and Koono.T. (1989) Comparisoii of human, simian, and bovmeroraviruses for requirement of slaUc aad in bemaggtntinauon and cell adsorpooa. Virology, 172.196-205.

415. Srhrtlrrf.B.. Qrou.H.-J.. Broixmcr.R.. HenfcH-D and Henier.G. (1990) rlinnagghninatmgenceplalotnyelms virus troches to N-«atyW-O*cayli)curamIiBc aad-comamint receptors oneiydiiucjtcs: Comparison wan bovine coronavirus and Influenza C virus. Wnu Ra., 16.183-15X.

416. TBvakxolA- and BomenA.T.H. (1990) Evidence for a direct role for sialic add ro tne •'••• '•••»<"of MM 1 |i>MioiDiMcaiu*His virus to Qumari erytnrocytes. Biodu*dary, 29, 10684—10690.

417. ScbohztJ., Cross JI.-J., BroasmerJL and Herrler.O. (1991) Tne Sprotcm of bovine cororawirusis a henajjtaanio recognlziia) 9-O-*cetybied sialic add as a receptor determinant../. VlwL. U,6232-6237.

418. CBictG.D., Tootood jM_, WQey.D.C. Skebd J J. and Knowies J.R. (1991) Ugand recognUooby irJtoenn virus. The bmomg of brvalent saVskks. / « o i CVCTL. 266. 23660-23669.

419. ScbakztM and Herrler.G. (1992) Bovine coiounlna tact ^-»cayl-»-O-«ceiylaeuramlnlc add asa receptor dennnmtnt to Initiate the mrecdon of cultured cells. / Go. VlroL, 73. 901-906.

420. Suzulri.Y.. Nagao.Y.. Kiro.H.. MauorDoro.M.. NeromcJC.. Naka£maJC and NotraawtE-(1986) Humas rnflwirra A virus h*m«gjindw4n distinguishes liaryloligosacchsriaes in tnembrane-

^ ai io receptor wliitli mediates the adsorption and fusion processes of virusinfection. Specifidty for oligosaccharides aad tiaUc adds and the K T ^ T ID wrocb sialic acidb attached. /. BwL Otm., 241. 17057-17061.

421. GenodU.R. and Padaj^.F. (19*5) Effect of Deunmtnitlaw treatment of cdb and effea of•olubk trvcoprtxeim on type 3 roorinu •^^*"—" to murine L cells. J. V\nL. 56. 336-364.

422. Utagaira£.T.. MiyanmraJL, Mukoyann^A, aad KonoJL (1982) Nenramimdase-sensiriveerytfuocyte iccepm for eumutiius type 70. J. Ctn. VlwL, 63. 141-148.

423. Zingala.B.. Carmol.C.. De UdertremcrJLM. and CoDi.W. (1987) Direct sialic add transferfrom a protein donor to grycolipiitt of trypomndgote forms of Trypamnmt crvi ttoL Blxhrm.PanuHoL, 26, 133-144.

424. Ubby.P. AlroyJ. andPtrerraJrf.&A. (1989) A norrarmnldase frrm Topoiiowiiiocnid remove!sialic add from the surftce of mammaliaii myocardnl and "••'""-"•I cells. J. CUn. brtB., 77.127-135.

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783. lamrs.S.P.. Murakawa.Y.. IJOof.M.E. and Berg.M. (1991) MnMplo rota of LcD-tTMEL-M laleokocyo: adhtsinn and ftmabm. hmaovL Ra.. 10. 282-292.

784. taal.Y.. L>sky.I_A. and RostnJ.O. (1992) Further dniauuUarlon of the imni'iimi betweeaL-seleam and in rmtnrhrHal hjands. CPycoototogy. 2. 373-381.

783. LaskyO-A.. Smger>l^., DowbenkoJ).. hmi.Y., Hemd.WJ., GrimSey.C. Frmrif.C.CaCmJ*.. WttsmuSJL and SoteaJJ). (1992) An «-tnttvdbl Djand (or L-adactin a a novelnodn-nkc rrmlrmln. CM, 69, 927-938.

786. GreenJM., TananmuT.. Wanmabo.T.. MryatalouM., HaaegawaJ^., KixxM.. Yue«,C.-T..StoDX^. aod Fcki.T. (1992) High affinity binding of rhe leucocyte adaoion molecule L-srifnfn to 3'-snlp!iaad-Leb rrd -Le. oHgotccchnrtoa rxd rhj predtniinEce of snlpfca to rMs

interaction demonstrated by trading studies with a series of lipid-unked oligosacchandes.Bkxhtm. Biookyi Ra. Comma.. 188. 244-251.

787 NorgardX. Hin.H.. Powdl.L.. Krkglerjtf., VarkiA. and Varki.N.M. (1993) Enhanced-.i.,.-.;™ of L-sdectm with me Ugh endorhdbl vennJc ligand via sdecovdy oxidized sialicacids. Pnx. Noll. Acad ScL USA. 90. 1068-1072.

788. St Joim,T., MeycrJ.. Idzerda,R. and GaDjnn.W.M. (1990) Expression of CD44 confer! a newadhesive phenotype oo li •"*'*• "d cdb. Cdl. 60. 45—52.

789 Arufrb.A.. StamenkovicJ.. MeUck.M.. UnderhiQ.C.B. and Setd.B. (1990) CD44 a theuiinUpal cdl surface icuvc m for byahtronate. Cdl. 61, 1303—1313.

790. Cullyjrf.. MlyakeX. Kincade.P.W.. SaorsatE., Botcher.E.C. and Undertun.C. (1990) Thenyahironaie receptor a a member of the CD44 (H-CAM) family of cdl surface glycoproteins.J. Cdl BioL, 111, 2765-2774.

79I.Serh>.. GoteJ_. Nagarkatn.M. and Nagarkani J> S. (1991) T-ceU-receptor-indepenoentactivation of cytotytic acdvity of cytotoxic T lymphocytes mediated through CD44 andgp9r/OL-" Pnx, NaL Acad. ScL USA. 88. 7877-7881.

792. LesleyJ.. He.Q.. MiyakeX. HamamA.. Hyman.JL and Kincade.P.W. (1992) Requirement!for hyaloronk add binning by CD44: A role for the cytopunmic domain and aarrauon byantibody. J. Exp. Utd.. 173. 257-266.

793. Cuhy J*.. NguyetuHA. and Underhm.C.B. (1992) The byaluronan receptor (CD44) parridpateiin the uptake and degradation of byaluronan. J. Cdl BtoL. 116. 1035-1062.

794. Tbcmas.L.. Byers.H.R., VtatJ. and StamenkovicJ. (1992) CD44H regulates mmor cdlmigration on hyaluronata-coated substrate. J. Cdl BioL, 118. 971-977.

795 Gunrhert,U.. HofmennX.. Riidy.W., Rcbo.S.. ZoUer.M.. HmmnumJ.. Matzku.S..Wenzd.A.. PooouH. and HerrlichJV (1991) A new variant of gtycopmein CD44 coofers••>• •••I«IL pntrtmal to rat carcinoma cdb. Cdl, 65, 13—24.

796. StamenkovicJ , SgroiJ).. Aruflb.A., Syjrf-S. and AndersoruT. (1991) The B lymphocyteadhesion motecale CD22 interacts with leukocyte common antigen CD45RO on T cdb and al-6snlyttransfense. CD75. on B cdb. Cdl, 66, 1133-1144.

797. StamenkovicJ., Sgroi.D. and Arurrb,A. (1992) CD22 binds to q-2.6-sialyllransferase-d>|» nrtnnepctopes on COS cdb. Cdl, 61. 1003-1004.

798. ArufrcA.. Kamer^.B.. SgroiJ}.. LedbetterJA. and StamenkovicJ. (1992) CD22-mediatedsrlrmittmnn of T cdb regulates T-ceU receptor/CD3-tnduced signaling. Pnx. NaiL Acad. ScLUSA, *9. 10242-10264.

799. Sgroi.D.. Varkj.A.. Braesch-Andersen ,S. and StamenkovicJ. (1993) CD22b. a B cell-specificbnmunoglobulin superfamay member b a sialic aad-bmding leclm J. BioL Ottm., a press.

800. PowdlJ-D., SgroiJJ., SJoberg.E.R., StamenkovicJ. and VarU.A. (1993) Natural Ugandt of theB cdl adhesion molecule CD22b carry N-linked oUgusacUiarides wUh a2.6 linked siaUc adds thatare required for pi'^gnhH'" / BioL Owm.. m press.

801. MorrbJ-, CrockerJ'.R., FnserJ.. HHlJrf. and OordonJ. (1991) Expression of a divalentcatjon-dependeot erythrobbm « i>*t » lojepmi by stromd macrophages rrom murina bonemarrow. / . Cdl ScL, 99. 141-147.

802. CnjckerJ>J(.. KdmJ.. Dubob.C. MarrmJ).. McWmiaawA.S., Shoaon,D^I., PanbonJ.Cand Gordon^. (1991) Purificatiaa and properties of ijalnarlhrtrn, a sialic add-bincBng receptorof munne dsue macrophages. EMBO J.. 19, 1661-1669.

803. V u den Berg.TX, BreviJJ.P.. DamobeauxJ.G.M.C. D6ppJJ-A.. KdmS.. CrockerJ'.R.,Ogkstra.C.D. and Kraal.G. (1992) qaloadhrrln on macrophages: In identification as alymphocyte adhesion molecule. / Eip. Utd.. 176. 647-655.

804. CrockerJ'.R.. WerbZ.. Gordon^, and Bainton.D.F. (1990) Uttrastrocmni kmliialkw of atrictcd sWk add binding hemagghtdnia, SER, in mauuv*iag<- buualupoictic ceD

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806. Utanan,M.A.. HaMwangerJIS. and HmjLL. (1986) Tba binding of fbcose-containbgglympnilriiii by hepatic learns The binding specificity of the rat Uver IOCOM lecdn. J. BioLOOWL. 261. 7426-7432.

(07. LehnnanJvl_A. and HU1.R.L. (1986) The binding of nicose-comaimng grycoprotdns by hepatici~^j~- PtmAcarjon of a rbcose-binding Icctin from rat Irvcr. J. BioL Chtm.. 261, 7419—7423.

808. LehnnenJ>4-A.. Pirro^.V.. ImberJH J. and Hill.R.L. (1986) The binding of rbcoav-containlnggrycoproteins by hepatic tectim: Re-examinarion of rha clearance from blood and die binding to

809. Shur j).D. and HaU.N.G. (1982) A role for mouse sperm surface gaUctosyttransferase in spermtinting to me egg zona peUudda. J. Cdl BioL. 95. 374-579.

810. ShurJI.D. (I9S3) Embryonal cardnoma ceO adhesion: die rote of surface gabctosyhnnsferaseand its 90K tadosamlnoglycin sobstnte. Drt. BtoL. 99. 360-372.

811. ScuOyJ4.F., ShaperJ.H. and Shur3.D. (1987) Spatial and temporal expressna of cdl surfacegali Mnjlimn^r^T* during mouse spuuiatugmms and epididymal maturation. Drt. BtoL. 124.111-124.

812. BaynaJlM.. ShaperJ.H. and SburJ.D. (1988) Temporally specific involvement of cdl surfacebeta-1,4 gabctosyltransferase during mouse embryo manna compacdon. CdL. 53. 143-157.

813. BetovacJ>.C. and Star J).D. (1990) Cdl surface gabctosyltransrerase mediates rbe bndatkm ofnenria outgrowth from PC12 cdb on htmimn. / Cdl BioL. 110. 461-470.

814. Begovac JVC. Hafl J5.E. and Shur3.D. (1991) Lamlnm fragment ES mediates PC12 cdl neurheoutgrowm by binding to ceD. surface 01.4 gabictosyltransferase. / . Cdl BioL. 113. 637-644.

813. Hathaway J iJ . and Shnr3.D. (1992) CeD surtace 01,4-fjlactosytaansferaje (unctions duringneural crest cdl migration and neurularioo in vivo. J. Cdl BioL, 117. 369-382.

116. MiDerJJJ.. MacefcM.B. aod Sbur3.D. (1992) ri«ii|a>ii« luarily between sperm surtace^1.4-fjlactDryl-transfeme and en-coat ZP3 mediates iptrm egg binding. Manor. 357.589-593.

817. Bsrcdlos-HofTJrf.H. (1992) Mammary ephfaefial leugaiilnlinn on ffiracrltulaT matrix bmnmated by cell surface galactosyllransferase. Eip. Cdl Ra.. 201, 225-234.

818. HamawayJIJ., RomagnanoJL-C and Babiarz,BJ. (1989) Analysb of ceO surfacegabuus/Uiausferase acdviry during motae tropbearjdcmnl difleremiatioa. On. BioL. 134,351-361.

819. rrmnphreys-BeherJrf.G.. Zefla.T.. M*edaJ4.. PurushothamXR- and Sctoerer.CA- (1990)as as a general modnnoor of m adnar ceD proiUeranon. HoL

CdL Biodttm.,95. 1-11.820. RomagnanoJ. and n«M«rT n (1990) The role of murina ceD 1 rfaa gala sfer

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822. KmtocxuS-A., Monfflo.S., Stew«n.CJ_ szd WtasarmmJ*. M. (1991) EmluyuAil un-iriimjcdb mnsfected wim ZP3 genes difTercmally glycosyuoa shrdlar pdypepnnes and secrett activeo m tpcrm roccpsr. /. Cdl BioL. 115, 655-664.

823. BteBJ.D. and WassarmanJ>.M. (1988) Gabctose at the i»mir<aiilng tuuikuu of O-UnkedoUgosaccharida of mouse egg ran p-""-"- (dvconroteln ZP3 b essential for the glyccprcsehi't

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126

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IC5. Cbtodrasekaran.S.. DeuJ. W.jn. Glmger.M.S. and Tanzer.M.L. (1991) Laminin carbo-hydrates ire lmplictted in cell signaling. J. CtU. Biochtm.. 4*. 115-124.

K26. GrttTon.C. Monsigny.M. end Kieda,C. (1991) Cell surface leams of human granulocytes: ibdraipicuiuu ts mortirUred by ranmdar cells and grtnulocyte/rnacrophage cosony-stunirlathighoof. OyaMototj. 1. 33-38.

K27. LeeJLT.. lchikawa,Y.. ADra.HJ. and Lee.Y C. (1990) Binding characteristics of gtlartrmrln-binding lectm (galapdo) from human spleen 7. fltoi O m , 265. 7864-7871.

ICH. AllenJlJ.. SOCBOJ).. GoamueJ.. K W h u i . . N i n j l . . PerndhJ^.. Casnllo.N. and Wilson.D.(IWlUiTr.llnrin.1 nfmtnfiw.ii ^.[^-..prtf-^njin, ttpjj j,, hnmtn .-.Hi inri m a g . 7n>UrBioL. 12. 52-60.

109. Cbenya.BJ., Wdner.SJ. ud PilW^. (1989) The Mac-2 antigen U • galactose-specific Iranthat binds igE. y. Eq> UaL. 178. 1959-1972.

H.W. RobensonX.W.. AIbrandl.K.. Kdler.D. and U u J -T. (1990) Hunan I|E-bindinf protein:A sorobte lectra exmbumg a highly conserved imrnrimn sequence and differential recognitionof IJE glyooforms. BtodKminrr, 29. 9093-1100.

K3I. Cher«)rO.BJ..ChahovtaJ..Woo|,C. and POlai J . (1990) Molecular dcoing of a human macro-phate lectio specific for galactose. Proc. Nad. Acod. ScL USA. 17. 7324-7328.

X32. Hyna.M.A.. OnM.. Baroodes.S.H . JesseTJ.T M. and BudU-B. (1990) Selective ciprauooof a rndogrnous lactose-balding lectin gene hi subsets of central aod [»it^r»l neurons.J. NanacL. 10. 1004-1013.

U3. Brassart,D . Kolodzlejczyt,E.. Grtnato.D.. Wota.A.. Pavulard.M.. PeronlJ.. Frigeri.LG..LmJ.-T., Bord.Y and NeeserJ.-R (1992) An intestinal galactme-speafic lectin mediatesthe binding of marine IgE to mouse •"'rrircil epithelial ceOs. Ettr. J. BuxMcm., 203,393-399

834. S»m.S. and Hughes.R.C. (1992) Binding speafiary of • baby hamster kidney tecdn for H typeI u d II rhaim. poljukctosamirje grycans, and appropriately grycosybtted forms of btrmnin andfibrooeain. J. BioL Otm.. 267, 6983-6990.

835. Hso.D.K.. ZubenJU. and Lm.F.-T. (1992) Biochemical and biophysical rhsrtnmTStioo ofhuman inmiiitniw igE-binding protein, an S-type animal lectin. J. BioL Oiam., 267.M167-14174.

836 PoirierJ.. runroomJ>.M., Chan,C.-T. J , OoeneU.-L. and RIgby.P.WJ. (1992) Expression oftbe L14 lectin diirm| mouse embryofenesa suggests multiple roles during prc- and post-implantatioa developroent. Drttiopmaa. 115, 143—155.

837. Iriinura,T., Mitlmhrra.Y.. SuooaJtC. Cirrtkro.D.. OnannesUn.D W., OearyJLR..OtaJ>.M., NkobccO.L. and LoauUt (1991) Increased content of an »i»iiit»~.n lactose-bmdiAg lectin in human colorectal carcinoma progressed to r~nrfmti* stages. Omar Ra., 5] ,3T7-393.

838. SahotO., W Q J . W . - C . , LoonJL and FnbxfcX. (1992) CMHcrential glycosylatioil and cellsurtact uprenion of lysosomal mrnJifaiy grycopnMems m snblines of a tnmtn colon canceroldbmng distinct metasntic poteadals. J. BioL Ottm.. HI, 5700-5711.

839. KochlerJ.. FraumodX.. SarbereX-L., VbcendoiuG. u d ZanenaJ.-P. (19S8) Cercbeflvsohibki lecdn is responsible for cell adbesioaand panidDUa In myctin compaction incolnired rttoUgodeodrocytei. Dn. NemnacL. 10, 199-212.

840. MmdMl j>.. Kceber^.. Neeset J.-R.. VuKendon.0. and ZanetnJ.-P. (1989) Carbohydrate andgrycoprnein specificity of mo mrtntemiri cerebellv lectta. BtacUmit. 71. 645-653.

841. Kochler^.. Herbem,G., SarlieveX.L.. VincodccG. md ZtnetoU-P. (1989) An endogmouslectin \Si.* htteracts wuh grycoprotein components is peripheral nervous system mydin. CtU.MdL BioL, 35, 581-596.

842. I rhnarm,.S., KnchterJ., Therenjnij^.. Vincendon,0. and Zanetoj.-P. (1990) An enttogenensIccdn and one of its Dearontl glycopioieui Ugands are inrotved In comet gnidanct of neuronmigration. Frx. Not AaxL ScL USA, 17. 6455-6459.

843. l x t a m i , KuchlerJ.. BHbche^.. ZacpfeUbf., Meyers, and ZanettaJ.-P. (1991)Iunil»mieul of the endogenous lecttn CSL tn adhesion of Chuiese hamster ovary cells. £ v J.Crfl«W.,5«, 433-442.

844. l u e r n j . , SUbertJ.E. and Cuh)J-A. (1983) CeO sar&ce heparas sutfne tae&MUa some adhesiveresponses to grjcosamfaofjycan-biafing matrices. Indudmj Rbrotactin. J. CtQ BioL, 9«,112-123.

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846. DrakfcS.U. IQein.DJ., MWOJISODJ) J., Oegtma.T.R., FurehtX-T. tnd McCanhyJ.B. (1992)CeUsnrfscephoiohatidylinrjstol-anchoralhcparMsdtoceU adhetioii to a fibroneafa-derired, beparWjindlng synthetic pepbde. J. CtU BioL. 117,1331-1341.

847. HangaUMC, McCanhyJ.B., RocheJC.F., Fnrcht,L.T. and Looumcau.P.C. (1992) CeMral andperipheral neuilte outgrowth dlfiers in prefcreace rbr heparin-bmding versus onegru>bindingsequences. J. NtmrascL, 11, 2034-2042.

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850. Dxvid.O., BaUC M.. Van dcr SchnerenJ.. r-^rim.- J..J. and Van den Bergbejl. (1992)DevehopmentaJ changes in beparan snlfats expression: In shn iVfrrrkm with mAbs. J. CtQ BtoL,119. 961-975.

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852. RoberDuD.D.. RJO.C.N.. LloaaJ-A.. GnlnickJUL and 01nsburg.V. (1986) Compuisoii of thespecificities of lammm, rhromboipondln. and von WlDebrand boor for binding to sulfatedgrjrcolipklj. J. BioL O m , Ml. 6872-6877.

853. RobernJXD.. Wniima^.B.. GraUiick.HJL and Omsborg.V. (1986) von WiUtbrand factorbinds spedficaDy to sulfimd grycohpids. / BioL Otm.. 241. 3306-3309.

854. Bobem,DJ5., HnrentickJJ.M.. Dait,v.M.. Frarier.W.A.. Santoro^.A. and Ginsburg.V.

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873. Misevic.G.N. and BurgerJil.M. (1990) The spedes-specific cdl-buiding she of tbe aggregationfactor from the sponge Mavdona proUftm a a tnghly repetitive oovd glycan mraarrringgtucuromc acid, fbcose. and matmose. J. BtoL Oitm.. US, 2Q577-2O584.

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875. Cairns J . and Morris.VJ. (1986) lnin inJn nlrr bindmg of xanrhan gum and ctrob pan. Afantrr.322. 89-90.

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ox December 31. 1992: accepted on January 19. 1993

130