blue-light photoreceptors in higher plants · 94305; e-mail: [email protected] eva huala...

P1: FHN/fgi P2: FHN

September 20, 1999 15:2 Annual Reviews AR092-02

?Annu. Rev. Cell Dev. Biol. 1999. 15:33–62

Copyright c© 1999 by Annual Reviews. All rights reserved

BLUE-LIGHT PHOTORECEPTORS

IN HIGHER PLANTS

Winslow R. BriggsDepartment of Plant Biology, Carnegie Institution of Washington, Stanford, California94305; e-mail: [email protected]

Eva HualaDepartment of Genetics, Stanford University School of Medicine, Stanford, California94305; e-mail: [email protected]

Key Words cryptochrome, flavoproteins, LOV domain, PAS domain, phototropin

■ Abstract In the past few years great progress has been made in identifying andcharacterizing plant photoreceptors active in the blue/UV-A regions of the spectrum.These photoreceptors include cryptochrome 1 and cryptochrome 2, which are simi-lar in structure and chromophore composition to the prokaryotic DNA photolyases.However, they have a C-terminal extension that is not present in photolyases and lackphotolyase activity. They are involved in regulation of cell elongation and in manyother processes, including interfacing with circadian rhythms and activating gene tran-scription. Animal cryptochromes that play a photoreceptor role in circadian rhythmshave also been characterized. Phototropin, the protein product of theNPH1gene inArabidopsis, likely serves as the photoreceptor for phototropism and appears to haveno other role. A plasma membrane protein, it serves as photoreceptor, kinase, andsubstrate for light-activated phosphorylation. The carotenoid zeaxanthin may serve asthe chromophore for a photoreceptor involved in blue-light-activated stomatal opening.The properties of these photoreceptors and some of the downstream events they areknown to activate are discussed.

CONTENTS

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34The Cryptochrome Family of Photoreceptors. . . . . . . . . . . . . . . . . . . . . . . . . 35

The Cryptochrome 1 Gene and Protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Components of Signal Transduction Downstream

from Cryptochrome 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Processes Mediated by Cryptochrome 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39The Cryptochrome 2 Gene and Protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Processes Mediated by Cryptochrome 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Cryptochromes in Other Photosynthetic Organisms. . . . . . . . . . . . . . . . . . . . . . . 42

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?34 BRIGGS ■ HUALA

Cryptochromes and Plant Circadian Rhythms. . . . . . . . . . . . . . . . . . . . . . . . . . . 43Cryptochromes in Animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Phototropin (nph1) and Related Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Phototropin(nph1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44The LOV Domains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Components of Signal Transduction Downstream from Phototropin. . . . . . . . . . . 48Arabidopsis NPL1 and Adiantum PHY3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

A Blue-Light Photoreceptor for Stomata. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Co-action Between Photoreceptor Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . 50

The Phototropism Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Cryptochrome Pathways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Action Spectra and Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52The Next Steps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

INTRODUCTION

Phototropism is the curvature of growing plant organs toward or away from asource of unilateral light. It is a classic plant response to blue light and has beeninvestigated for more than a century. Charles Darwin (1881) first showed thatred light did not induce this curvature response, and it was Julius von Sachs in1883 (see Sachs 1887) who measured the first crude action spectrum with coloredglass and colored solutions, demonstrating that wavelengths in the blue region ofthe spectrum were among those that did induce a response. These phototropismstudies were carried out more than half a century before the first demonstration thatlonger wavelengths of light could affect plant development. Flint (1934) and Flint& McAlister (1935, 1937) were the first to report experiments showing that redlight promoted lettuce seed germination and that far-red light inhibited it. Flint& McAlister’s work formed the genesis of an entire field of research that wassubsequently designated photomorphogenesis. Their work has led to our presentknowledge of the phytochrome family of photoreceptors and the physiological,biochemical, and molecular consequences of conversion of the red-absorbing form,Pr, to the far-red-absorbing form, Pfr (Batschauer 1998, Chamovitz & Deng 1996,Fankhauser & Chory 1997, Quail et al 1995, Quail 1997, Whitelam & Devlin 1998).Butler et al (1959) used biochemical and spectral techniques to demonstrate thatphytochrome was a chromoprotein. By contrast, research on the nature of blue-light photoreceptors lagged behind. It was only in 1993 that Ahmad & Cashmorereported the first sequence for cryptochrome 1 (cry1), a chromoprotein that servesas a blue-light photoreceptor. [We use here the notation style recommended forthe phytochromes (Quail et al 1994): e.g. cry1 for the holoprotein, CRY1 for theapoprotein,CRY1for the wild-type gene, andcry1 for the mutated gene.]

Although there was an enormous literature on the many physiological, biochem-ical, and molecular responses of plants (as well as fungi and algae) to blue lightprior to 1993 (for reviews, see Briggs & Iino 1983; Jenkins et al 1995; Kaufman

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?BLUE-LIGHT PHOTORECEPTORS 35

1993; Senger 1980, 1984, 1987; Senger & Briggs 1981; Short & Briggs 1994),there was anything but agreement as to what might be the nature of the blue-light-absorbing chromophore. Candidate chromophores were carotenoids (Qui˜nones &Zeiger 1994, Qui˜nones et al 1996, Shropshire 1980, Wald & du Buy 1936), flavins(Galston 1949, 1950), pterins (Galland & Senger 1988), and even retinal (Lorenziet al 1994). Briggs et al (1957) rejected Galston’s proposal for flavins when theyfound that the hypothesized differential flavoprotein-mediated destruction of thegrowth hormone auxin across a unilaterally irradiated plant organ did not oc-cur. (However, involvement of flavins in other mechanisms was not considered.)Palmer et al (1996) later rejected carotenoids because maize coleoptiles devoidof detectable carotenoids responded to unilateral blue light with normal pho-totropic curvature (and blue-light-activated phosphorylation, see below). Actionspectroscopy was of no particular help in identifying the chromophore (Briggs &Iino 1983). What later came to be called the cryptochrome-type action spectrum-asingle broad action band in the UV-A and a band with fine structure in the blue–wasused by both the carotenoid and flavin camps to support their candidates. Thiswas because it showed spectral properties that were characteristic of each putativechromophore (fine structure in the blue, typical of carotenoids, and a broad peakin the UV-A, typical of flavins and flavoproteins). Biochemistry failed to resolvethe issue, and a genetic approach was clearly in order.

Since the seminal paper by Ahmad & Cashmore (1993), research on blue-light receptors has rapidly accelerated, as indicated by the spate of recent reviews(Ahmad & Cashmore 1996, Batschauer 1998, Cashmore 1997, Cashmore et al1999, Chamovitz & Deng 1996, Fankhauser & Chory 1997, Jenkins et al 1995,Jenkins 1997, Khurana et al 1998, Lin & Cashmore 1996, Liscum & Hangarter1994, Ninnemann 1997, Whitelam & Devlin 1998). In the present review, wefirst summarize research on three recently characterized blue-light photoreceptorsin plants, cryptochrome 1 (cry1), cryptochrome 2 (cry2), and phototropin (nph1,the photoreceptor for phototropism), and review progress in the identification ofa fourth blue-light photoreceptor, which mediates light-activated stomatal open-ing. We discuss studies in which mutants have implicated specific photoreceptorsin various downstream signaling steps and processes and briefly treat the inter-action of pathways activated by different photoreceptors. We also review studieson organisms other than plants where sequence comparisons indicate evolutionaryconservation of specific domains and include the recent work on cryptochromesand their possible function in animals.

THE CRYPTOCHROME FAMILY OF PHOTORECEPTORS

It was Gressell (1977) who coined the term cryptochrome to refer to the thenunidentified photoreceptor(s) with the cryptochrome-type action spectrum de-scribed above. The tacit assumption was that the cryptochrome family of pho-toreceptors would be related proteins, as are the phytochromes, and would share a

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common chromophore. Thus Lin et al (1995a) referred to the putative photorecep-tor protein encoded by theHY4 locus, described by Ahmad & Cashmore (1993),as cryptochrome 1 or cry1. (Earlier-described mutant alleles at this locus are stilldesignatedhy4, but more recently described alleles are designatedcry1.) The dis-covery of the gene for a closely related protein, cryptochrome 2 or cry2, and thepreliminary characterization of its protein product (Hoffman et al 1996, Lin et al1996b) solidified the cryptochrome nomenclature in the literature. We return tothe question of nomenclature for blue-light photoreceptors in a subsequent section.

The Cryptochrome 1 Gene and Protein

Mutations at theHY4 locus in Arabidopsis fail to show blue-light-induced inhibi-tion of hypocotyl elongation (Koornneef et al 1980). Ahmad & Cashmore (1993)isolated a T-DNA-tagged mutant,hy4-2, allelic with the originalhy4allele,hy4-2.23N, from Koornneef’s laboratory, permitting them to clone and sequence thewild-type HY4gene. The gene encodes a 681-amino acid protein with sequenceidentity near 30% with prokaryotic DNA photolyases over the N-terminal 500amino acids. Identities are as high as 70% or more over domains involved inchromophore binding in the photolyases. Identification of mutations in theCRY1sequences of three otherhy4alleles [plus many more subsequently characterized(Ahmad et al 1995)] confirmed the identification of the gene.

At its C-terminal end, cry1 has an extension, found in none of the photolyases,that shows some relatedness to rat smooth muscle tropomyosin. However, thisextension lacks the predictedα-helicity characteristic of tropomyosin, making itdifficult to evaluate the functional relevance of the similarity (Ahmad & Cashmore1996). Nevertheless, seven of the alleles have mutations in this region (Ahmad &Cashmore 1993, Ahmad et al 1995), suggesting its importance for cry1 function.Because the photolyases serve as photoreceptors mediating light-activated repairof pyrimidine dimers in UV-damaged DNA, Ahmad & Cashmore (1993) proposedthat the hy4 holoprotein was itself a photoreceptor, mediating blue-light-inducedinhibition of hypocotyl elongation.

Photolyase activity was unlikely to account for cry1 action on elongation growthbecause the protein lacks a specific tryptophan (W277 inEscherichia colipho-tolyase) that is conserved in all prokaryotic photolyases and is required for bindingthe enzyme to the damaged DNA (Li & Sancar 1990). Indeed, subsequent workfailed to detect cry1 photolyase activity (Lin et al 1995b, Malhotra et al 1995).Pang & Hays (1991) had already demonstrated photolyase activity in Arabidopsisboth in vivo and in vitro, and Ahmad et al (1997) recently cloned and character-ized a single-copy gene, designatedPHR1, that encodes a protein similar to animaltype II photolyases. Complementation of anE. coliphotolyase mutant withPHR1and identification of an Arabidopsis mutant lacking photolyase activity and witha lesion in thePHR1gene, demonstrated that phr1 was an authentic photolyase.Surprisingly, the gene showed little sequence similarity, either with the prokaryotictype I photolyases or with the cryptochromes.

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Photolyases all have flavin adenine dinucleotide (FAD) and either a deazaflavinor a pterin as the chromophore (Sancar 1994). Cry1 was found to bind the expectedFAD (Lin et al 1995b, Malhotra et al 1995). Thus Galston’s original hypothesis(1949, 1950) that a flavin could serve as the chromophore in a plant photore-ceptor has finally been confirmed. Although flavin-binding domains are in mostcases poorly conserved, there is some conservation within the photolyases. Theflavin-binding domains of photolyases using deazaflavin as a second chromophoreshow greater sequence similarity to others using a deazaflavin than those using apterin (see Malhotra et al 1992 and references therein) and vice versa. Althoughthe sequence similarity of the chromophore-binding domain originally indicatedthat cry1 might bind a deazaflavin as its second chromophore (Lin et al 1995b),Malhotra et al (1995) found it to be the pterin methenyltetrahydrofolate (MTHF)at least for the protein produced by the expression ofHY4 in E. coli. If cry1 invivo also binds MTHF, the first blue-light photoreceptor characterized would thenhave two of the four originally proposed chromophore molecules.

Subsequent studies from the Cashmore laboratory provided evidence for thehypothesis that cry1 was a true photoreceptor (Ahmad & Cashmore 1993). First,Arabidopsis itself is something of an oddity in that several responses are elicitedby green light in addition to blue and UV-A light (phototropism: Konjevi´c et al1989, 1992; hypocotyl inhibition: Young et al 1992). Lin et al (1995b) noted underredox conditions that might be found in plant cells, cry1 holoprotein formed a stableflavosemiquinone with significant absorption in the green. Second, overexpressionof cry1 in tobacco gave the seedlings a dramatic increase in the sensitivity forinhibition of the hypocotyl not just to blue and UV-A but green light as well(Lin et al 1995a). Examination of several over-expressing lines showed that theamount of increased hypocotyl inhibition compared with wild-type was closelycorrelated with the degree of over-expression. Third, over-expression of cry1 inArabidopsis also caused hypersensitivity to all three wavelength regions (Lin et al.1996a). Together with cry1’s obvious similarities in structure and chromophoreswith the DNA photolyases, known to be photoreceptors, these observations leavelittle doubt that cry1 functions as a photoreceptor.

Cry1 appears to be a soluble protein (Lin et al 1996a), although it remainspossible that a fraction may be membrane associated (Ahmad et al 1998b). It isexpressed both in dark-grown Arabidopsis seedlings and in all organs of maturelight-grown plants (Ahmad & Cashmore 1993). Protein levels of cry1 in Arabidop-sis are unaffected by white light treatment (Lin et al 1996a), and in this sense, theArabidopsis chromoprotein is analogous to phyB, which is light stable (see Quail1991).

Components of Signal Transduction Downstreamfrom Cryptochrome 1

To date, nothing is known about the earliest events following cry1 photoexcitation.Based on analogy with the photolyases, it seems likely that signal transduction may

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be initiated by an electron transfer reaction (see discussions in Ahmad & Cashmore1997, Jenkins et al 1995, Malhotra et al 1995). Indeed, cry1 contains the tryptophancorresponding to W306 inE. coli. In the prokaryotic photolyases, this tryptophandonates an electron to photoexcited FADH to generate FADH− as an early eventin the repair mechanism (see Sancar 1994). If such electron transfer is involvedwith the plant photoreceptor, cry1 is using a signal transduction mechanism thatdiffers from other known mechanisms such as protein conformational change,phosphorylation, changes in protein-protein interaction, and G-protein activation(Malhotra et al 1995). Given the complex photochemical properties of flavins(and pterins), the proposal is reasonable. However, there are still no hints as to apossible cryptochrome reaction partner in the putative redox reaction.

Elements further down the signal-transduction pathway have been identified,however. A large number of Arabidopsis mutants have been described that show alight-grown phenotype when grown in darkness. These include thecop(constitu-tive photomorphogenesis) anddet (de-etiolated phenotype) mutants. Many ofthese mutants were subsequently found to be identical to the previously describedfus( fusca) mutants selected because they showed intense accumulation of antho-cyanin pigments in darkness. Mutations at thecop/det/fusloci are all recessive,and because they show the phenotype of a light-grown plant, the gene products ofthese loci are thought to act as repressors of photomorphogenesis (see reviews byBatschauer 1998, Chamovitz & Deng 1996, Fankhauser & Chory 1997, Whitelam& Devlin 1998).

Extensive work by Deng and associates has shown that the products of a numberof these genes are required to suppress the developmental pattern normally seenin light-grown seedlings. Furthermore, they must block those components ofphotomorphogenesis that are specifically activated by photoexcitation of phyA,phyB, and cry1. For example,cop1mutations are epistatic not just to phytochromemutations such ashy1, hy2, andhy3, but also tohy4 (cry1) (Ang & Deng 1994).Likewise, cop8, cop10, andcop11(Wei et al 1994) andcop12( fus12), cop13( fus11), cop14( fus4), cop15( fus5), anddet1 ( fus2) (Kwok et al 1996) are allepistatic to the phytochrome andcry1 mutations. Finally, overexpression of theCOP1gene inhibits normal photomorphogenesis in the light (McNellis et al 1994),and overexpression of an N-terminal fragment of COP1 has a dominant-negativeeffect on light-mediated seedling development (McNellis et al 1996), consistentwith the hypothesis that COP1 acts as a repressor of photomorphogenesis.

The current model is that COP1, plus probably the DET1 protein and otherproteins, is localized in the nucleus in the dark. These proteins associate with alarge complex designated the COP9 complex, which is constitutively localized inthe nucleus and contains 12 subunits. Some of these subunits have been shownbe related to human counterparts, suggesting that the COP9 complex may play ageneral role in eukaryotic development (Chamovitz et al 1996). In the light, COP1moves out of the nucleus to the cytoplasm, where it binds COP-interacting protein1 (CIP1) (Matsui et al 1995). The various genes involved in photomorphogenesis,whether regulated by blue or red light through the cryptochrome or phytochrome

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photoreceptors, respectively, are thought to be derepressed when COP1 is absentfrom the nucleus (Chamovitz & Deng 1996, Chamovitz et al 1996). Recent stud-ies indicate that phyA, phyB, and cry1 are all involved in a somewhat complexfashion in triggering the COP1 migration in the light (Osterlund & Deng 1998).How signals arriving from the different photoreceptors converge on a single reg-ulatory complex and become subsequently repartitioned to mediate different andsometimes completely unrelated responses remains a puzzle.

Processes Mediated by Cryptochrome 1

In addition to regulating hypocotyl elongation, cry1 mediates many other pro-cesses. Mutants at theHY4 locus showed decreased cotyledon expansion, in-creased petiole elongation, increased flower stem elongation, and increased leafexpansion in light-grown seedlings (Jackson & Jenkins 1995). Interestingly, ex-cision ofhy4cotyledons prior to irradiation eliminated the mutant phenotype, andthe cotyledon response to blue light was similar to the response of cotyledonsexcised from wild-type seedlings. The results suggest that the cry1 signal must betransmitted to the cotyledons from another part of the seedlings (Blum et al 1994).Thehy4mutants also showed decreased formation of anthocyanins (Ahmad et al1995, Jackson & Jenkins 1995) and reduced blue-light-induced accumulation ofthe mRNAs for enzymes such as chalcone synthase (CHS) (Ahmad et al 1995,Fuglevand et al 1996, Jackson & Jenkins 1995), chalcone isomerase (CHI), anddihydroflavonol reductase (DFR) (Jackson & Jenkins 1995), all catalysing stepsearly in the phenylpropanoid pathway. At least forCHS, blue-light induction wasindependent of phyA and phyB, although both phytochromes have absorption inthe blue region of the spectrum (Batschauer et al 1996). In addition to regulatingthe transcription of genes encoding enzymes early in the phenylpropanoid path-way, cry1 is also required for full expression ofGAPA, GAPB (genes encodingglyceraldehyde-3-phosphate dehydrogenases A and B), andrbcS, three nucleargenes encoding chloroplast proteins (Conley & Shih 1995).

Transgenic Arabidopsis seedlings over-expressingCRY1showed correspond-ingly increased steady-state levels ofCHSmRNA and increased accumulation ofanthocyanins in response to UV-A, blue, and green light (Lin et al 1996a). Thesetransformants showed pleiotropic effects on seedling morphology, with shorterpetioles, smaller rosettes, reduced leaf size, and shorter inflorescence stems, in di-rect contrast to the effects found inhy4mutants (see above). The over-expressingtransgenics also showed slightly delayed flowering. However, this response couldbe a function of the ecotype (Wassilewskija). In Columbia, mutants deficient incry1 showed greatly delayed flowering under a daylength extension enriched forblue light or following night interruptions with blue light (Bagnall et al 1996).

Some time ago blue light was shown to induce a rapid and strong inhibitionof elongation growth in etiolated seedlings (onset of inhibition within minutes orseconds of the start of irradiation) (Cosgrove 1981, Gaba & Black 1979, Meijer1968). The inhibition is transient and the growth rate recovers upon return to

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darkness. Blue light, even in brief pulses, can also induce a lasting inhibitionof growth, but this inhibition is separable from the rapid inhibition. In etiolatedpea seedlings, the long-lasting inhibition does not begin until many hours after ablue-light pulse and persists for many more hours (Warpeha & Kaufman 1989),whereas the rapid and transient response shows a lag of only 2–3 min (Laskowski& Briggs 1989).

Blue light also activates a dramatic and rapid depolarization of the plasmamembrane in etiolated seedlings (Spalding & Cosgrove 1988). This depolariza-tion precedes the rapid inhibition of growth and shows the same fluence-responsecharacteristics, suggesting that the depolarization is causally related to the growthresponse. Initially this effect was thought to be mediated by light activation ofa H+-ATPase (Spalding & Cosgrove 1992). However, subsequent work demon-strating blue-light activation of an anion channel sensitive to the inhibitor 5-nitro-(3-phenylpropylamino)-benzoic acid (NPPB) (Cho & Spalding 1996) called theearlier interpretation into question. Lewis et al (1997) later showed this activationto follow a calcium-independent pathway. NPPB also strongly inhibited blue-light-induced accumulation of anthocyanins in Arabidopsis, but curiously failedto show any effect on blue-light-induced increases in the levels of phenylalanineammonia lyase 1 (PAL1), CHS, CHI, or DFR mRNA, or proteins (Noh & Spalding1998). Hence, blue-light induction of anthocyanin accumulation must involvemore than one blue-light-activated pathway, at least one of which is indepen-dent of the transcriptional activation of the appropriate genes, but involves anionchannel activation.

As with the COP/DET/FUS complex, mutants are helping to elucidate which ofthe above responses are mediated by the cry1 photoreceptor. Using both intracel-lular and surface-contact electrodes, Parks et al (1998) found blue-light-induceddepolarization to be greatly reduced (though not eliminated) in the Arabidopsiscry1 null mutanthy4-2.23N. However, the rapid inhibition of growth was unaf-fected in the mutant. Only a longer-term growth inhibition was affected by the lossof cry1 protein. NPPB mimicked the effect of thecry1mutation: It had no effect onthe rapid inhibition of growth by blue light but blocked the longer-term response. Itis not clear whether the Arabidopsis long-term response is similar to that describedfor pea, as the latter has a much longer lag period (Warpeha & Kaufman 1989).

In a closely related study, Wang & Iino (1997) carried out elegant photobiologi-cal investigations of a blue-light-induced transient shrinking of protoplasts isolatedfrom maize coleoptiles grown under continuous red light. A blue-light pulse alsotransiently inhibited the elongation of intact coleoptiles, and in both cases the ki-netics were not dissimilar to those for the rapid inhibition of stem growth. As withthe depolarization response reported by Cho & Spalding (1996), NPPB completelyinhibited the shrinking response. Wang & Iino (1998) investigated the same phe-nomenon in protoplasts from red-light-adapted Arabidopsis hypocotyls. As withthe coleoptile protoplasts, NPPB strongly inhibited the light-induced shrinking.The shrinking response was absent in thehy4-1mutant, implicating cry1 directlyin the response. Despite the relative rapidity of the response, however, it can not

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be directly related to the rapid inhibition of growth because this latter inhibition isunaffected inhy4mutants (Parks et al 1998). At present the nature of the photore-ceptor(s) mediating the rapid inhibition of growth and the residual depolarizationin cry1mutants discussed above remains unresolved. It will be of interest to carryout studies similar to those of Parks et al (1998) and Wang & Iino (1997, 1998)with Arabidopsiscry2andnph1mutants (see below).

The Cryptochrome 2 Gene and Protein

TheCRY2gene in Arabidopsis encodes a protein of 619 amino acids with exten-sive similarity to cry1 in the photolyase-like domain (Lin et al 1996b, designatedcry2; Hoffman et al 1996, designated AT-PHH1). Like cry1, cry2 has a C-terminalextension that is not found in the photolyases. However, the cry2 extension showsno similarity to that of cry1. Batschauer (1993) cloned a gene from white mustard(Sinapis alba, SA-PHR1, later designatedSA-PHH1), originally thought to be aplant photolyase. Later work failed to confirm photolyase activity (Malhotra et al1995), and both SA-PHH1 and cry2, like cry1, lack the conserved tryptophan cor-responding toE. coliphotolyase amino acid W277 (Malhotra et al 1995, Hoffmanet al 1996). SA-PHH1 is 89% identical to Arabidopsis cry2 at the protein level,although unlike either Arabidopsis CRY protein, it lacks a C-terminal extension(Hoffman et al 1996). The chromophore composition of cry2 is currently not fullyresolved, although Lin et al (1996b) report that cry2 binds a flavin.

Arabidopsis cry2 is a soluble protein found throughout the seedling and, un-like cry1, it is strongly down-regulated by blue (but not red) light (Lin et al 1998).Down-regulation presumably occurs at the protein level because mRNA abundanceis unaffected by blue-light treatment (Lin et al 1998, Ahmad et al 1998a). Reg-ulation is at the level of protein stability and not at the level of protein synthesis(Ahmad et al 1998a). In this sense, cry2 differs from phyA, in which down-regulation by light occurs both at the protein and mRNA levels (see Quail 1991).Because the down-regulation is unaffected incry1 mutants, either cry2 itself orsome other blue-light photoreceptor must mediate the response (Lin et al 1998).

To a certain extent cry1 and cry2 have overlapping functions. A number ofchimeric proteins with C-terminal and N-terminal domains swapped between Ara-bidopsis cry1 and cry2 complemented Arabidopsishy4-3, a mutant lacking cry1,both in hypocotyl inhibition and anthocyanin formation (Ahmad et al 1998a).Chimeric constructs containing cry2 sequences, whether C-terminal or N-terminal,were unstable in vivo as previously reported for cry2 itself under blue-light treat-ment (see above). However, cry1 from tobacco, unlike cry1 from Arabidopsis,is unstable (Ahmad et al 1998a). Hence the stability properties found for theArabidopsis cryptochromes are not ubiquitous.

Processes Mediated by Cryptochrome 2

Like cry1, cry2 plays a role in blue-light-induced suppression of stem growth.Lin et al (1998) examined both seedlings over-expressingCRY2andcry2deletion

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mutants (see Guo et al 1998) for blue-light inhibition of hypocotyl elongation andstimulation of cotyledon opening. For the deletion mutants, sensitivity was lostin the lower but not in the higher fluence-rate range. By contrast,cry1 mutantsshowed loss of sensitivity (hypocotyl elongation) only in the high fluence-raterange. Seedlings over-expressing either cry1 or cry2 showed enhanced growthinhibition by blue light (Lin et al 1998). Hence at least for the Arabidopsis cryp-tochromes, as with the phytochromes, there is one pigment (cry2 or phyA) sensitiveto very weak light signals and one sensitive to strong signals (cry1, phyB).

Cry2 also plays a major role in photoperiodic timing. Seedlings carryingcry2mutations show greatly delayed flowering on long days or in continuous light, andthecry2 mutation is allelic to the previously described late-flowering mutantfha(Guo et al 1998). Expression of theCONSTANS(CO) gene, a transcriptional factorrequired for long-day promotion of flowering in Arabidopsis, also depends uponcry2/fha. Seedlings over-expressingCRY2show increased levels ofCOmRNA onboth short and long days, andcry2mutants show reduced levels, especially on longdays. Additional mutant studies indicated that cry2, acting as a positive regulatorof CO gene expression, mediates the blue-light inhibition of phyB function (Guoet al 1998). More detailed studies involving both single and doublecry mutantssupport this hypothesis and also indicate that the roles of cry1 and cry2 are at leastpartially redundant (Mockler et al 1999). Mockler et al (1999) also showed thatresponses to light quality are elicited only during the first seven days followinggermination, with flowering time independent of light quality thereafter. Thus boththe cry1 and cry2 photoreceptors play a role in flowering, a process once thoughtto be exclusively controlled by phytochrome in photoperiodically regulated plantspecies (see Vince-Prue 1994).

Cryptochromes in Other Photosynthetic Organisms

Cryptochromes are likely to be ubiquitous in higher plants and have been identifiedin tomato, pea, and rice (see Ahmad & Cashmore 1996). Kanegae & Wada (1998)identified five genomic clones from the fernAdiantum capillus-veneriswith se-quence similarity to cry1 and obtained evidence that at least three of these wereexpressed. Given the extraordinary complexity of fern photobiological phenom-ena (Wada & Sugai 1994), the presence of several cryptochromes is not surprising.Like the Arabidopsis cryptochromes, the predicted fern proteins have C-terminalextensions, but these sequences bear little relationship to the Arabidopsis exten-sions (or to each other).

Likewise, Small et al (1995) have isolated aChlamydomonascryptochromegene,CPH1, encoding a putative CRY protein. It shares 43% identity with SA-PHH1 and 49% identity with Arabidopsis cry2. Like both cry1 and cry2, it hasa C-terminal extension. This extension shares little similarity with either of theArabidopsis CRY sequences, and Small et al propose that the extension may pro-vide the specificity to interact with the next component in the signal transductionpathway. It seems reasonable that these downstream components are different for

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the individual cryptochromes. As with the higher-plant cryptochromes, neithertheChlamydomonasnor theAdiantumCRY proteins have the tryptophan corre-sponding to W277 inE. coli photolyase.

Cryptochromes and Plant Circadian Rhythms

Cry1 has recently been shown to play a role in perceiving light signals that affectthe oscillator driving circadian rhythms. The mRNA for catalase 3 (CAT3) inArabidopsis shows circadian oscillations that dampen to a high steady-state mRNAlevel in darkness. In the Arabidopsishy4-2.23Nmutant, which lacks a functionalcry1 protein (Ahmad & Cashmore 1993), no damping was observed over 96 h ofcontinuous darkness (Zhong et al 1997). Hence cry1 is in some way required forthe damping. In another study, Somers et al (1998) crossed various Arabidopsisphotoreceptor mutants (phyA,phyB,cry1, andcry2) with transgenic plants carryingthe firefly luciferase gene under the control of the ArabidopsisCAB2promoter.This construct is highly responsive to the circadian clock (Millar et al 1992).Using plants carrying the construct, Millar et al demonstrated that acry1 mutantshowed significant lengthening of the free-running period forCAB2expressionover wild-type. Somers et al (1998) determined free-running period length undercontinuous red or blue light at various fluence rates. Over-expression ofCRY1significantly shortened the free-running period at high fluences of blue or whitelight, whereas loss of cry1 resulted in period lengthening over both high and lowfluence-rate ranges. From these studies, Somers et al (1998) concluded that phyB isthe predominant high-intensity red-light photoreceptor, phyA is the low-intensityred-light photoreceptor, and that both cry1 and phyA perceive and transmit blue-light signals to the clock. The small effects of cry2 are thought to be indirect.

Cryptochromes in Animals

In the last four years, interest inCRYgenes and proteins has spread well beyondthe realm of plant research with the isolation ofCRYgenes from humans, mice,andDrosophila. The human geneshCRY1andhCRY2were first isolated as poten-tial photolyase genes [as with SA-PHH1, the cryptochrome from white mustard(Batschauer 1993)] in an effort to address the ongoing controversy over whetherhumans have photolyases (Adams et al 1995, Hsu et al 1996, Todo et al 1996, vander Spek et al 1996). Like the plant cry1, the human cry proteins carry two chro-mophores: FAD and a pterin (Hsu et al 1996). The HCRY1 and HCRY2 apopro-teins are 73% identical at the amino acid level. As with the plant cryptochromes,they diverge completely in their C-terminal extensions, which are about 80 aminoacids long.

It was later shown that the human cry1 and cry2 proteins exhibit no photolyaseactivity, although unlike the cry proteins discussed above, they appear to have bothof the essential tryptophan residues (corresponding to theE. coliW277 and W306)required for photolyase activity (Hsu et al 1996). Hsu et al therefore proposed thatthese cry proteins might function as blue-light photoreceptors in humans. One

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indirect piece of evidence supporting this hypothesis is the reported interactionof the C-terminal portion of human cry2 (hcry2) with the serine/threonine phos-phatase PP5, a protein similar to the RdgC protein phosphatase involved in signaltransduction arising from rhodopsin photoexcitation (Zhao & Sancar 1997).

More direct evidence came from the work of Miyamoto & Sancar (1998), whoshowed that the mouse homologues (mCRY1andmCRY2) of the human genesare expressed in the mouse retina. Furthermore,mCRY1expression oscillates in acircadian rhythm within the superchiasmatic nucleus (SCN) where the master clockis thought to reside. This work, together with the observation that the Arabidopsiscry proteins participate in light signaling for circadian rhythms and photoperiodictiming (see above), led to the proposal that these newly identified mammalianphotoreceptors set the phase of the circadian clock (Miyamoto & Sancar 1998).To test the function of mcry1 more directly, a mouse mutant lacking this genewas developed and found to have a phenotype consistant with a mcry1 role inmodulating circadian photoreception. This phenotype included reduced photicsensitivity, enhanced phase shifts in response to light pulses, and, as with anArabidopsiscry1mutant (Millar et al 1995), lengthening of the free-running period(Thresher et al 1998).

More recently a singleCRYgene has also been cloned fromD. melanogaster.Like mCRY1, its protein product appears to have a role in resetting the circadianrhythm (Emery et al 1998). A mutant in this gene,cryb, fails to show a phase shiftin response to short intense light pulses. Thecryb mutation shows a synergisticeffect on disruption of circadian rhythms in anorA(blind) background, suggestingthat the clock receives input from both mcry1 and rhodopsin. This mutation alsodisrupts the cycling of the molecular clock components PER and TIM in certaintissues. However, in contrast to the Arabidopsis and mousecry mutations, therewas no lengthening of the free-running period (Stanewsky et al 1998).

PHOTOTROPIN (nph1) AND RELATED PROTEINS

Phototropin (nph1)

Just over a decade ago, Gallagher et al (1988) first reported the blue-light-activatedphosphorylation of a plasma membrane protein in etiolated pea seedlings. Shortand Briggs (1994) discussed the known biochemical and photobiological propertiesof this system, so they are only briefly summarized here. The protein is likely tobe ubiquitous in higher plants, ranging from 114 to 130 kDa, depending uponthe species. The phosphorylation reaction can be driven both in vivo and in vitro,the latter providing a convenient assay for biochemical characterization. Lightactivates the kinase function rather than exposing sites for phosphorylation througha protein conformational change. Phosphorylation occurs on multiple serine andthreonine residues. Although the reaction requires Mg+2, it is Ca+2 independent. Itis highly ATP specific, and the protein itself has an ATP-binding site. It can functionas a dimer, and the phosphorylation is at least partially intermolecular between thedimer partners. The system also possesses a biochemical memory for a light pulse

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at least in vitro where light activation of phosphorylation can be detected afterseveral minutes of darkness following the light treatment.

A great deal of physiological evidence suggests that the light-induced phospho-rylation of the plasma membrane protein is involved in phototropism (see Short& Briggs 1994): it occurs in the most photosensitive tissue, its action spectrummatches that for phototropism, it is sufficiently fast to precede curvature develop-ment, it shows the same dark-recovery kinetics as phototropism following a satu-rating light pulse, and both the phosphorylation and phototropism obey the rules forfirst order photochemistry. Finally, Salomon et al (1997a,b) have demonstrated agradient in in vivo phosphorylation across coleoptiles unilaterally illuminated bycertain fluences of blue light, with more phosphorylation on the illuminated thanthe shaded side. These results are the first demonstration of a light-induced bio-chemical gradient that might be directly associated with phototropism. Studieswith Arabidopsis mutants (Liscum & Briggs 1995) provided direct genetic evi-dence that the phosphoprotein plays a central role in phototropism. Certain mutantsnull for a phototropic response in growing organs from both light-grown and dark-grown seedlings (including the negative phototropic response of roots) showed nolight-induced phosphorylation and completely lacked the plasma membrane phos-phoprotein. The mutant locus was designatednph1(non-phototropichypocotyl),and the authors hypothesized that the nph1 protein might be the photoreceptor forphototropism.

Photobiological and mutant studies showing differences in Arabidopsis pho-totropic responses to blue and green light (Konjevi´c et al 1989, 1992) led the Poffgroup to propose that there were two separate photoreceptors coupled in somefashion. Becausenph1null mutants lack phototropic sensitivity to both blue andgreen light, Liscum & Briggs (1995) presented instead a model involving a singlephotoreceptor with two chromophores, perhaps analogous to the situation with theDNA photolyases.

Although there was indirect evidence to suggest that the nph1 protein itself isa photoreceptor, substrate, and kinase for the phosphorylation reaction (Short &Briggs 1994), it remained a possibility that the three functions could be ascribedto two or even three different polypeptides. The cloning and sequencing of Ara-bidopsisNPH1(Huala et al 1997) resolved the kinase question: the nph1 protein(996 amino acids) contained all 11 of the signature sequences for serine-threoninekinases (Hanks & Quinn 1991, Hanks et al 1988). Mutations in the sequencesof threenph1alleles confirmed that theNPH1gene encoded the phosphoprotein.The nph1 protein itself is hydrophilic and lacks any membrane-spanning domains(Huala et al 1997). The association with the plasma membrane is most likelythrough some sort of hydrophobic interaction, but the biochemical nature of theassociation is currently unknown.

Three slightly smaller homologues of Arabidopsis nph1, two closely relatedones fromAvena sativa(Zacherl et al 1998) and one fromZea mays(GenBankAccession No. AF033263), were subsequently cloned. These proteins showedmore than 70% identity with the Arabidopsis protein, and more than 85% identityover the two related domains designated LOV1 and LOV2 (for light, oxygen, and

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voltage (see below). As predicted by earlier biochemical studies (Reymond et al1992), the maize and oat proteins were significantly smaller than the Arabidopsisprotein, lacking several stretches of amino acids in the N-terminal domain. Partialnph1 sequences have also been reported for pea (Lin et al 1991, Lin & Watson1992), ice plant (Mesembryanthemum crystallinum) (Bauer et al 1994), and spinach(GenBank Accession No. X73298).

Christie et al (1998) resolved the photoreceptor question by demonstrating thatnph1 expressed in insect cells grown in the dark exhibited blue-light-activatedphosphorylation with the same fluence dependence and kinetics as the native Ara-bidopsis protein. Large amounts of FMN accumulated in the insect cells producingnph1, which led the authors to propose that FMN was the chromophore for the re-action. As the fluorescence excitation spectrum of the recombinant protein closelymatched the action spectrum for phototropism (Baskin & Iino 1987), Christie et alconcluded that nph1 was the photoreceptor for this response. An argument fre-quently expressed in favor of a carotenoid rather than a flavin as the chromophoreof a blue-light photoreceptor was that flavoprotein absorption spectra lack the sharppeaks in the blue found in typical cryptochrome-type action spectra. However, suchfine structure is typically found in the absorption spectra of carotenoids (Quiñoneset al 1996). Evidently the binding of FMN to the NPH1 apoprotein provides a re-stricted hydrophobic environment that leads to its more sharply defined absorptionspectrum and hence the characteristic action spectrum for phototropism. Rüdiger& Briggs (1995) found that the thio reagentN-phenylmaleimide was far moreeffective in inhibiting light-induced phosphorylation than the more hydrophilicN-ethylmaleimide, consistent with this model. Christie et al (1999) have designatedthe holoprotein nph1 phototropin.

A recent paper from the Cashmore laboratory (Ahmad et al 1998b) reported thatcry1cry2double mutants failed to show first positive phototropic curvature and thatmembrane preparations failed to show blue-light-induced phosphorylation. Thisevidence suggested that the cryptochromes were involved in phototropism. How-ever, Lascève et al (1999) have shown that such double mutants (as well ascry1andcry2single mutants) respond to blue-light fluences inducing first positive curvatureover the same fluence range as wild-type. In addition, the double mutants exhib-ited wild-type sensitivity for blue-light-induced phosphorylation. Both single anddouble mutants showed somewhat reduced curvature, but no difference from wildtype in threshhold, peak, or saturation fluences. Hence in the absence of eitherCRY protein, the seedlings still detected and responded to light direction, and therole of the CRY proteins, if any, must be downstream of nph1. It is possible that theprotocol used by Ahmad et al (1998b) did not optimize the very weak first posi-tive phototropic response of Arabidopsis, accounting for the differences observed.

The LOV Domains

A sequence found both in the N-terminal and central regions of the nph1 proteinis also present in proteins from an extremely diverse group of organisms. This do-main, found in light sensors, oxygen sensors, and the eag family of voltage-gated

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potassium channel proteins, has been designated LOV, as mentioned above (Hualaet al 1997). Light sensors carrying a LOV domain include nph1 (Huala et al1997) and white collar 1 (WC-1), a putative blue-light sensor from the filamen-tous fungusNeurospora crassathat is required for blue-light-dependent responses(Ballario et al 1996). Oxygen sensors include a bacterial regulator of nitrogen fix-ation (NIFL) (reviewed by Dixon 1998), an aerotaxis protein (AER) fromE. coli(Bibikov et al 1997), a methyl-accepting protein fromDesulfovibrio vulgaris(Fu et al 1994), and a regulator of bacteriorhodopsin production (BAT) fromHalobacterium halobium(Gropp & Betlach 1994, Shand & Betlach 1991). Theeag potassium channel family group includes a large number of eag, elk, and ergsubunit proteins fromDrosophilaand a variety of vertebrates. Although the activ-ity of these potassium channels is voltage-regulated, one member of the family, theHERG(human ether-a-gogo related gene) potassium channel was recently foundto be oxygen-regulated (Tagliatela et al 1997).

The LOV domain sequence bears some similarity to a PAS domain (Zhulin& Taylor 1997), but there is a much higher degree of sequence similarity amongLOV domains than between LOV and PAS domains (Huala et al 1997, Ballarioet al 1998), suggesting that LOV domains form a subgroup within the larger groupof PAS domains. Like PAS domains, LOV domains can interact to form dimers(Ballario et al 1998). In the WC-1 protein, the LOV domain alone is capable offorming a dimer with another LOV domain but can dimerize only very weakly witha PAS domain. In addition, three mutations isolated in the WC-1 LOV domainfailed to prevent LOV dimerization but still blocked WC-1 function, implying anadditional function for this domain (Ballario et al 1998). Unlike the WC-1 protein,the isolated LOV domain from the human potassium channel geneHERGdoesnot multimerize (Cabral et al 1998). Interestingly, a human mutation (11261) inwhich only the portion of HERG containing the LOV domain is expressed resultsin a dominant phenotype of sudden cardiac death in juveniles as well as adults.This appears to result from the assembly of mutant and wild-type subunits into anabnormal potassium channel which results in a heart malfunction in heterozygousindividuals (Li et al 1997).

LOV domains can also serve as flavin-binding sites. Of the proteins containinga LOV domain, NIFL fromAzotobacter vinelandiiwas the first to be identified asa flavoprotein containing FAD (Hill et al 1996). More recently, S¨oderback et al(1998) narrowed the FAD-binding domain to the N-terminal 284 amino acids, aregion spanning the NIFL LOV domain. Since then, AER has also been shownto bind FAD (Bibikov et al 1997, Grishanin & Bibikov 1997, Rebbapragada et al1997). The sequence similarity between NIFL, AER and nph1 in the region ofthe LOV domains led to the hypothesis that they might function as flavin-bindingsites (Huala et al 1997, Rebbapragada et al 1997).

Christie et al (1999) have recently demonstrated that the LOV domains of nph1are capable of binding the flavin FMN when expressed as isolated domains in aheterologous expression system. When they expressed either LOV1 or LOV2 sep-arately inE. coliand purified the recombinant peptide, they found that both LOV1and LOV2 domains bound FMN with a flavin/protein ratio of 1. Expression of a

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larger construct containing both LOV domains bound FMN with a ratio approach-ing 2. These findings are consistent with the two-chromophore model proposedby Liscum & Briggs (1995).

The crystal structure of the human HERG LOV domain, known as the eagdomain, has been determined (Cabral et al 1998), as well as the FixL LOV do-main forBradyrhizobium japonicum(Gong et al 1998). In both cases, the LOVdomain forms a ß-sheet core flanked byα-helices making a hydrophobic pocketthat is capable of binding a ligand. The hydrophobic pocket is accessible forligand binding via a hydrophilic entryway. In the case of the FixL domain, theligand is known to be a heme, although the authors point out that the structure issufficiently flexible to accommodate a range of cofactors. The PAS domains fromthe bacterial photoactive yellow protein (PYP) form similar structures (Genicket al 1997, Pellequer et al 1998). As with the HERG and FixL LOV domains,a ß-sheet core flanked byα-helices is also involved, but in this case the ligandis a 4-hydroxycinnamyl chromophore, present in the hydrophobic pocket of thebarrel-like structure in both ground and photoactivated states (Genick et al 1997).This pocket-containing structure is also found in other flavin-binding domains(Liepinsh et al 1998), although in these cases there is little homology with theLOV domains (WR Briggs & E Huala, unpublished observations).

Components of Signal Transduction Downstreamfrom Phototropin

Unlike the case with the cryptochromes, mutations at theNPH1locus do not showa pleiotropic phenotype. They are impaired in all of their phototropic responses,but there are no other obvious differences from wild-type. In their mutant studies,Liscum & Briggs (1995, 1996) report three additional loci affecting phototropism.For two of these loci, designatedNPH2andNPH3, normal levels of phototropinare present, and nph1 phosphorylation proceeds normally, although phototropismis impaired. Hence the gene products encoded by these loci must act downstreamfrom nph1 in the phototropism signal transduction pathway. The third additionallocus,NPH4, is impaired in both phototropism and gravitropism (Liscum & Briggs1996). NPH4 appears to be a conditional modulator of auxin-induced differentialgrowth responses and is deficient in auxin-induced gene expression (Stowe-Evanset al 1998). The identification of theNPH2, NPH3, andNPH4 genes and thefunctions of their encoded proteins should enhance our knowledge of signal trans-duction in phototropism.

Arabidopsis NPL1 and Adiantum PHY3

Jarillo et al (1998) recently reported aNPH1homologue in Arabidopsis designatedNPL1 (NPHl-l ike) that encodes a protein slightly shorter than nph1 (916 aminoacids compared with 996 for nph1). It shows approximately 58% identity and67% similarity with nph1 at the amino acid level and contains LOV1, LOV2,and kinase domains. Although it is expressed (having been cloned from a cDNAlibrary), its role as a photoreceptor is not clear. Null mutants at theNPH1locus fail

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to show any phototropic curvature (Liscum & Briggs 1995, Lasc`eve et al 1999),though presumablyNLS1is being expressed. Alternatively, perhaps phototropismdepends upon a functional dimer (Reymond et al 1992) that requires both geneproducts, possibly because in the absence of one protein the other is unstable orinactive. This explanation seems unlikely as the nph1 protein expressed in insectcells shows normal stability and photoactivity in the absence of any other plantproteins (Christie et al 1998).

Nozue et al (1998) recently described a remarkable gene from the fernAdiantumcapillus-veneris(AcPHY3) that encodes a protein with properties of two differentphotoreceptors: phytochrome and nph1. The amino-terminal 564 amino acidsshow 52% identity with Arabidopsis phyA and include the signature phytochromechromophore-binding domain. When the authors expressed the full-length apopro-tein in yeast and added the chromophore phycocyanobilin, the chromophore be-came bound as assayed by zinc-blot analysis, and showed typical phytochromephotoreversibility as determined by a Pr minus Pfr difference spectrum. However,the similarity with phytochrome in the N-terminal region abruptly ends at aminoacid 564. Dimerization domains and other features of a typical phytochrome aremissing, and instead, the C-terminal portion of the protein shows 57% identity withArabidopsis nph1, including both LOV domains and the complete serine/threoninekinase domain. As with the LOV domains from Arabidopsis and oat nph1, thosefrom Adiantumprotein also bind FMN tightly (Christie et al 1999). Given thecomplexity of fern responses to both blue and red light (reviewed by Wada &Sugai 1994), it is tempting to hypothesize that PHY3 plays a photoreception rolein both red and blue spectral regions. It will be interesting to see whether thePHY3 protein undergoes light-activated phosphorylation. If so, are both blue andred light able to induce it? Alternatively, does red light transformation of thephytochrome domain to its Pfr form alter the properties of the phosphorylationreaction? Further, does phosphorylation affect phytochrome phototransformationproperties in any way?

A BLUE-LIGHT PHOTORECEPTOR FOR STOMATA

It has been known for two decades that very small amounts of blue light inducethe opening of stomata via excitation of a photoreceptor that is independent ofphotosynthesis or phytochrome (Iino et al 1985, Travis & Mansfield 1981; seeZeiger & Zhu 1998b for review). The swelling of isolated guard cell protoplasts inresponse to blue light indicated that the blue-light photoreceptors were located inthe guard cells (Zeiger & Hepler 1977). However, the nature of the photoreceptorremained unknown. An action spectrum by Karlsson (1986) showed fine structurein the blue region of the cryptochrome type, but because measurements were madeonly as far as 370 nm, little could be said about the presence or absence of a broadaction band in the UV-A region.

Guard cells contain a functional xanthophyll cycle (Masamoto et al 1993),considered to be an important component for photoprotection in chloroplasts

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(Demmig-Adams & Adams 1992). However, there is a close correlation betweenfluence rate and the concentration of guard cell zeaxanthin, a relationship notfound in mesophyll cells (Srivastiva & Zeiger 1995a). Dithiothreitol (DTT)inhibits zeaxanthin formation (Yamamoto & Kamite 1972) and inhibits stom-atal opening induced by blue light but not by red (Srivastiva & Zeiger 1995b).This and other correlative evidence implicating zeaxanthin as the photoreceptorfor blue-light-activated stomatal opening has been reviewed by Zeiger & Zhu(1998b).

Recently, Niyogi et al (1998) described an Arabidopsis mutant,npq1(for non-photochemicalquenching) that lacks violaxanthin de-epoxidase and is thereforeunable to convert violaxanthin to zeaxanthin (a reaction normally occurring un-der high light conditions). Zeiger & Zhu (1998a, 1998b) tested the responsesof wild-type andnpq1mutant seedlings for blue-light-induced stomatal openingunder increasing background levels of red light. Wild-type stomata showed astrong increase in the blue-light-activated opening response with an increasingfluence rate of the background red light. By contrast, thenpq1mutant showed nochanges in stomatal aperture regardless of the red-light fluence rate. These experi-ments support the hypothesis that zeaxanthin may play a role as the photoreceptorchromophore for stomatal opening.

CO-ACTION BETWEEN PHOTORECEPTOR SYSTEMS

A response to photoexcitation of one plant pigment system may be modified byphotoexcitation of another, or indeed may even require this additional photoexcita-tion for full expression of a given response (for a detailed review, see Mohr 1994).Here we consider recent papers in which studies with mutants have elucidatedthese relationships with respect to specific photoreceptors.

The Phototropism Pathway

Phytochrome phototransformation in dark-grown seedlings dramatically altersphototropic responses to blue light, sometimes in an extremely complex man-ner (Iino 1990). First positive curvatures of coleoptiles are de-sensitized, whereassecond positive curvatures are sensitized (see Briggs 1963a). By contrast, thereis no change in sensitivity of Arabidopsis hypocotyls (threshold fluences are un-changed), but the magnitude of the curvature response is enhanced (Parks et al1996). Partial photoreversibility by far-red light (coleoptiles: Briggs 1963b;Arabidopsis: Janoudi & Poff 1992) and an action spectrum for the effect (coleop-tiles: Chon & Briggs 1966; Arabidopsis: Janoudi & Poff 1992) established thatthis response is phytochrome mediated.

Studies with phytochrome mutants showed that phyA is responsible for thered light enhancement of first positive phototropism at low fluences of red light(Janoudi et al 1997, Parks et al 1996), that phyB played no role, and that the

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response to higher fluences of red light must be through some phytochrome otherthan phyA or phyB (Parks et al 1996). For the enhancement observed in Ara-bidopsis for second positive curvature, however, both phyA and phyB playedan important role (Hangarter 1997). Bothcry1cry2andphyAphyBdouble mu-tants show reduced first positive curvature, making it possible that the CRY andPHY photoreceptors play a role in determining the magnitude of the phototropicresponse. Alternatively, physiological differences arising from differences in con-ditions for seed development and harvest between mutants and wild-type couldaccount for the reduction (Lasc`eve et al 1999).

Cryptochrome Pathways

Interactions between cry1- and phyA- or phyB-activated signal transduction path-ways are complex. A number of studies have investigated potential interactions asrevealed by single, double, and triple mutants at theCRY1, PHYA, andPHYBloci.Results differ widely depending upon growth conditions, frequency and/or dura-tion of red- or blue-light treatments, the fluence rates used, and the response studied(seed germination, inhibition of hypocotyl elongation, hook opening, cotyledonunfolding, cotyledon expansion, or anthocyanin synthesis). Under some conditionscry1 can function independently of the phytochromes, but under other conditionsits action depends heavily on one or the other or both. Space limitations precludea detailed discussion of these studies, and the reader is referred to recent articlesand references therein for further information and analysis (Ahmad & Cashmore1997, Casal & Boccalandro 1995, Casal & Mazzella 1998, Neff & Chory 1998,Poppe et al 1998). As yet there are no studies that have includedcry2 mutants.Furthermore, other phytochromes function even in the absence of phyA and phyB(Poppe & Sch¨afer 1997), and their role in blue-light-activated signal transductionremains unexplored.

Yeh & Lagarias (1998) recently demonstrated light-regulated autophosphory-lation of eukaryotic phytochrome, indicating that phytochrome could function asa protein kinase. Ahmad et al (1998c) used purified recombinant photoreceptorsto investigate whether cry1 serves in vitro as a substrate for phyA-mediated phos-phorylation. Cry1 alone showed no phosphorylation in response to light. In thepresence of phyA in the dark, there was limited phosphorylation of both cry1 andphyA, but both red and blue light increased the phosphorylation of both photore-ceptors (phosphorylation was also reported following far-red light, but the resultswere not shown, nor was far-red reversibility tested). Cry1 phosphorylation waslocalized to serine residues in the C-terminal domain. Similar results were ob-tained with recombinant cry2. In addition, yeast two-hybrid studies indicated adirect interaction between the C-terminal domains of cry1 and phyA. Moreover,in vivo phosphorylation studies showed Pfr-dependent phosphorylation of cry1.However, it is premature to speculate as to how these intriguing findings relate tothe physiological studies mentioned above, although they provide the first evidencefor a possible direct interaction between photoreceptors.

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ACTION SPECTRA AND NOMENCLATURE

A curious paradox arises from the use of the term cryptochrome for the photolyase-like blue-light photoreceptors. Gressel specifically used it to designate a photore-ceptor for which the action spectrum resembles the absorption spectrum of aflavoprotein or acis-carotene (known to have a small absorption in the UV-A).At least for cry1, it seems unlikely that this action-spectrum requirement is met.Both Ahmad & Cashmore (1993) and Young et al (1992) show strong UV-A actionin the suppression of hypocotyl elongation in Arabidopsis mutants lacking cry1despite virtually complete loss of sensitivity to blue light. Hence, only a fraction ofthe UV-A sensitivity may be related to cry1. Indeed, the UV-sensitivity found bothin the mutant and wild-type seedlings is likely to be mediated through a specificUV-A sensor and not through cry1 (Young et al 1992). Cry1 must contribute someUV-A photosensitivity, however, as cry1 overexpression either in tobacco (Lin et al1995a) or Arabidopsis (Lin et al 1996a) results in increased sensitivity to UV-A.

With pterin-type photolyases, the pterin largely determines the action spectrumfor light-driven DNA repair (Sancar et al 1987). Absorbed light energy is trans-ferred to the FAD chromophore that initiates the repair reaction. The FAD itselfcan act as a chromophore for the reaction, but is approximately tenfold less effec-tive (Jorns et al 1987, 1990). The pterin in vivo normally absorbs largely in theUV-A, but Malhotra et al (1994) have described a photolyase fromBacillus firmusthat shows action well into the blue region of the spectrum. If the cryptochromesutilize a photochemical mechanism that is similar to that used by the photolyases,then the action spectra for cryptochrome-dependent processes would be expectedto reflect largely the pterin absorption spectrum and not that of the FAD. The actionof green light could still be ascribed to the semiquinone form of FAD, as proposedby Lin et al (1995b). The limited information available for the action spectrum forsuppression of hypocotyl elongation in Arabidopsis suggests that this may be thecase. A careful action spectrum for wild-type,cry1, cry2, andcry1cry2mutantseedlings of Arabidopsis is clearly needed to clarify the situation.

The following paradox has arisen: If the above hypothesis is correct, thencryptochromes that do not yield a cryptochrome-type action spectrum have pre-empted the cryptochrome name. Phototropin, with its cryptochrome-type actionspectrum, but absolutely no structural similarity to the cryptochromes and with adifferent chromophore can not be called a cryptochrome!

THE NEXT STEPS

Although astonishing progress has been made over the past several years in char-acterizing blue-light photoreceptors such as cry1, cry2, the animal cryptochromes,and phototropin, much remains to be done. A present there is little or no infor-mation about events in the signal transduction cascades immediately downstreamfrom the various photoreceptors. At this writing, not a single interacting reaction

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partner has been identified. Once such partners have been identified, it will be nec-essary to determine in what way(s) chromophore excitation leads to downstreamevents. With the plant photoreceptors, there is increasing evidence of participa-tion of the COP9 nuclear complex in signal transduction both for cryptochrome-and phytochrome-elicited processes. However, how the specificity for the variousresponses is retained downstream of these complexes remains a mystery. The cur-rent list of plant photoreceptors responding to blue and ultraviolet light is not likelyto be complete. Beyond the identification of a putative chromophore in the stom-atal guard cells, there is still much to learn. What is the nature of the interactionsdetected between pathways that are activated by different photoreceptors? Why arethere interactions between two photoreceptors in some cases, but independent ac-tion in other cases? What is the nature of this signaling network? As mentionedabove, there is evidence for a specific UV-A photoreceptor independent of cry1,and there is also strong evidence for at least one UV-B photoreceptor (Teramura1996, Christie & Jenkins 1996). What are these photoreceptors? How are thevarious photoreceptors coupled to the circadian oscillator? The coming decadewill offer some exciting advances as we probe for a deeper understanding of pho-tomorphogenesis in plants and the photobiological aspects of circadian rhythmsin both plants and animals.

ACKNOWLEDGMENTS

The authors are extremely grateful to Drs. John M Christie, Margaret A Olney,and Richard Walden for their careful review of this manuscript. Work discussedfrom the senior author’s laboratory was generously supported by the NationalScience Foundation. This is Carnegie Institution of Washington Department ofPlant Biology Publication No. 1413.

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Annual Review of Cell and Developmental Biology Volume 15, 1999

CONTENTSVacuolar Import of Proteins and Organelles from the Cytoplasm, Daniel J. Klionsky, Yoshinori Ohsumi 1

Blue-Light Photoreceptors In Higher Plants, Winslow R. Briggs, Eva Huala 33

Cooperation Between Microtubule- and Actin-Based Motor Proteins, Susan S. Brown 63

Molecular Mechanisms of Neural Crest Formation, Carole LaBonne, Marianne Bronner-Fraser 81

Lymphocyte Survival--The Struggle Against Death, Robert H. Arch, Craig B. Thompson 113

The Road Less Traveled: Emerging Principles of Kinesin Motor Utilization, Lawrence S. B. Goldstein, Alastair Valentine Philp 141

Proteins of the ADF/Cofilin Family: Essential Regulators of Actin Dynamics, James R. Bamburg 185

Visual Transduction in Drosophila, Craig Montell 231

Biochemical Pathways of Caspases Activation During Apoptosis, Imawati Budihardjo, Holt Oliver, Michael Lutter, Xu Luo, Xiaodong Wang

269

Regulation of Nuclear Localization: A Key to a Door, Arie Kaffman, Erin K. O'Shea 291

Actin-Related Proteins, D. A. Schafer, T. A. Schroer 341

Cell Polarity in Yeast, John Chant 365

Vertebrate Endoderm Development, James M. Wells, Douglas A. Melton 393

Neural Induction, Daniel C. Weinstein, Ali Hemmati-Brivanlou 411

SCF and CDC53/Cullin-Based Ubiquitin Ligases, R. J. Deshaies 435Integration of Signaling Networks that Regulate Dictyostelium Differentiation, Laurence Aubry, Richard Firtel 469

When to Switch to Flowering, Gordon G. Simpson, Anthony R. Gendall, Caroline Dean 519

Regulation of Mammalian O2 Homeostasis by Hypoxia-Inducible Factor 1, Gregg L. Semenza 551

Mechanisms of Viral Interference with MHC Class I Antigen Processing and Presentation, Jonathan W. Yewdell, Jack R. Bennink 579

Transport Between the Cell Nucleus and the Cytoplasm, Dirk Görlich, Ulrike Kutay 607

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[PSI+]: An Epigenetic Modulator of Translation Termination Efficiency, Tricia R. Serio, Susan L. Lindquist 661

Adaptors for Clathrin-Mediated Traffic, Tomas Kirchhausen 705

Synaptic Vesicle Biogenesis, Matthew J. Hannah, Anne A. Schmidt, Wieland B. Huttner 733

The Translocon: A Dynamic Gateway at the ER Membrane, Arthur E. Johnson, Michael A. van Waes 799

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blue-light photoreceptors in higher plants · 94305; e-mail: [email protected] eva huala...

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