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Download Collagen. Objectives Structure 1- Structure of collagen Distribution 2- Distribution of collagen Functions 2- Functions of collagen Biosynthesis 3- Biosynthesis

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  • Slide 1
  • Collagen
  • Slide 2
  • Objectives Structure 1- Structure of collagen Distribution 2- Distribution of collagen Functions 2- Functions of collagen Biosynthesis 3- Biosynthesis of collagen Degeneration 4- Degeneration of collagen Diseases 5- Diseases of collagen (Clinical Applications)
  • Slide 3
  • collagen What is collagen ? most abundant protein Collagen is the most abundant protein in the human body. fibrous protein Collagen is a fibrous protein structural functions Collagen serves as having structural functions in the body. Collagen is found in components of Skin - Skin - Connective tissue - Connective tissue - Blood vessel walls - Blood vessel walls - Sclera & cornea of the eye - Sclera & cornea of the eye
  • Slide 4
  • general structure general structure of collagen primary & secondary levels Collagen protein has primary & secondary levels of structure. A typical collagen molecule is a long, rigid structure in which three polypeptides ( chains) are wound around one another triple helix. in a rope-like triple helix. Types and organization of collagen molecules are governed by the structural role collagen plays in a particular organ. a gel vitreous humor in some tissues, collagen is dispersed as a gel as in the vitreous humor of the eye. parallel fibres tendons in other tissues, collagen may be arranged in parallel fibres that provide great strength as in tendons corneastacked in cornea of eye, collagen is stacked so as to transmit light.
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  • Types Types of collagen Collagen super family of proteins includes more than 20 collagen types three polypeptide chains The three polypeptide chains are held together by hydrogen bonds between chains chains ~1000 amino acids chains are ~1000 amino acids long but with slightly different properties chains These chains are combined to form the various types of collagen found in tissues.Examples: Type 1 collagen Type 1 collagen: Most common collagen contains two 1 chains and one 2 chain 1 2 2 1 2 2 Type II collagen Type II collagen: contains three 1 1 3 1 3
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  • types most abundant types of collagen
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  • detailed structure detailed structure of collagen Amino acid sequence 1- Amino acid sequence proline glycine Collagen is rich in proline & glycine Proline : by its ring structure facilitates the formation of the helical conformation of each chain. Glycine Glycine (smallest amino acid): present in every third position of the chain. It fits into the spaces where the three chains of the helix come together. [-Gly- X Y ] Glycines are parts of a repeated sequence [-Gly- X Y ] where: XY Hydrox X is frequently Proline Pro & Y is often Hydroxyproline Hyp (can be Hydroxylsine Hyl) So, most of the chain can be POLYTIPEPTIDE with sequence of: (- Gly- Pro Hyp -) 333
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  • Triple-helical structure 2-Triple-helical structure Collagen as a fibrous protein has an elongated, triple-shaped helical structure in which side chains (R- groups) of its amino acid are on the surface of the triple-helical molecule. This allows bond formation between the exposed R-groups of neighbouring collagen monomers resulting in their aggregation into long fibres. detailed structure detailed structure of collagen (cont.)
  • Slide 12
  • hydroxyproline & hydroxylysine 3- hydroxyproline & hydroxylysine Hydroxyproline hydroxylysine Hydroxyproline & hydroxylysine are not present in most proteins, however, collagen contains them. These two amino acids result from the hydroxylation of some proline & after their incorporation lysine amino acids after their incorporation into poly peptide chains during protein biosynthesis. (i.e. post-translational modification) Hydroxyproline Hydroxyproline is important in stabilizing the triple-helical structure of collagen because it increases (maximises) interchain hydrogen bond formation. detailed structure detailed structure of collagen (cont.)
  • Slide 13
  • Proline is hydroxylated by prolyl hydroxylase enzyme which requires ascorbic acid (vitamin C) ascorbic acid (vitamin C) as a coenzyme detailed structure detailed structure of collagen (cont.)
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  • glycosylation 4- glycosylation The hydoxyl group of hydroxlysine amino acids of collagen may be glycosylated by enzymatic reaction. Glucose & galactose molecules are attached to the polypeptide chain prior to triple helix formation. detailed structure detailed structure of collagen (cont.)
  • Slide 15
  • biosynthesis biosynthesis of collagen The polypeptide precursors intracellularly The polypeptide precursors of collagen molecules are formed intracellularly in fibroblasts (or in osteoblasts of bone & chondroblasts of cartilage) & then secreted into the extracellular matrix. mature collagen monomers In the extracellular matrix, mature collagen monomers are formed. Collagen monomers aggregate & become cross-linked to form collagen fibrils.
  • Slide 16
  • intracellular stage (in fibroblasts) Formation of pro- chain 1- Formation of pro- chain (protein biosynthesis on ribosomes of RER) Hydroxylation of some proline & lysine amino acids 2- Hydroxylation of some proline & lysine amino acids on Y-position of Gly X Y sequence of pro- chain by enzymes prolyl & lysyl hydroxylases (requires vitamin C) In cases of vitamin C deficiency (Scurvy): In cases of vitamin C deficiency (Scurvy): Hydoxylation of proline & lysine will not occur, with no cross linking resulting in decrease in the tensile strength of collagen fibers. Clinical manifestations Clinical manifestations: bruises in the limbs due to subcutaneous extravasation of blood (capillary fragility) Glycosylation 3- Glycosylation: some hydroxylysine amino acids are glycosylated by glucose or glucose-galactose Assembly & Secretion 4- Assembly & Secretion; Pro- collagen form procollagen which is a precursor of collagen that has a central region of triple helix, flanked by non-helical amino and caboxy- terminal extensions of the pro- chain. Procollagen molecules are translocated to the Golgi apparatus where they are packaged in the secretory vesicles which fuse with cell membrane causing the release of procollagen into extracellular space. biosynthesis biosynthesis of collagen (cont.)
  • Slide 17
  • Intracellular Stage of Collagen Synthesis (in fibroblasts)
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  • Bruises in lower limb in a case of scurvy
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  • Extracellular Stage (in matrix) Extracellular cleavage of procollagen molecules: 5- Extracellular cleavage of procollagen molecules: Procollagen molecules are cleaved by N- & C- procollagen peptidases tropocollagen which remove the terminal nonhelical peptides resulting in the formation of triple helical tropocollagen molecules. molecules. Formation of collagen fibrils: 6- Formation of collagen fibrils: collagen fibril Individual tropocollagen molecules associate to form a collagen fibril. Collagen fibril form an ordered, overlapping, parallel array with adjacent collagen molecules in a staggered pattern. Cross-link formation of collagen fibrils 7- Cross-link formation of collagen fibrils lysyl oxidase by the enzyme lysyl oxidase which oxidatively demainates some lysine and hydroxylysine amino acids in collagen forming aldhydes. An aldehyde from one collagen polypeptide link with lysine or hydroxylysine amino acids of mature collag a neighboring collagen polypeptide to form covalent cross-links resulting in mature collagen formation. biosynthesis biosynthesis of collagen (cont.)
  • Slide 20
  • Extracellular Stage of Collagen Synthesis (in matrix) Collagen Fibril Tropocollagen (Collagen molecule) Procollage n
  • Slide 21
  • Collagen Fibril Collagen Molecule
  • Slide 22
  • Cross-links formation in collagen Aldhyde group formed on one collagen polypeptide NH2 of lysine on neighbor collagen polypeptide Cross-link between adjacent collagen polypeptides
  • Slide 23
  • degradation degradation of collagen several years Half-lives of normal collagen are several years. collagenases Collagen fibrils is degraded by collagenases (matrix metalloproteinases) that cleave a collagen molecule into two fragments 3/4 & length. other matrix proteases Then by other matrix proteases, these fragments are degraded to individual amino acids.
  • Slide 24
  • collagen diseases genetic disease Defects in any one of the steps of collagen fibre synthesis can result in a genetic disease involving inability of collagen to form fibres properly (& thus collagen will not provide tissues with the needed tensile strength). 1000 mutations More than 1000 mutations have be identified in 22 genes coding for 12 of the collagen types.
  • Slide 25
  • collagen diseases (cont.) Ethlers-Danlos syndrome (EDS) Results from inherited defects in the metabolism of fibrillar collagen molecules. EDS can result from EDS can result from: Deficiency in collagen-processing enzymes as lysyl hydroxylase deficiency or procollagen peptidase deficiency Mutations in the amino acid sequences of collagen type I, II, III, or type V. (most important mutations are in of genes for type III) notdegradedaccumulated Collagen containing mutant chains is not secreted. So, it is degraded or accumulated in cells. Clinical Manifestations: Lethal v

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