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55 Cards in this Set
- Front
- Back
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What is the most common protein in the body?
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Collagen:
- 80% of non-mineral content - 75% of dry weight in skin |
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What amino acid pattern is found in collagen?
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- Gly-X-Y triplet repeats
- X is frequently proline - Y is frequently hydroxy-proline |
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What is the 3D organization of collagen?
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- 3 collagen molecules form right handed helical segments
- Can be made of 3 of the same alpha-collagen chains or two or three different alpha-collagen chains |
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What are the main classes of collagens?
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1. Fibril-forming / Fibrillar
2. FACIT (Fibril-Associated Collagens with Interrupted Triple helices) 3. Collagen Type IV 4. Beaded Filament 5. Collagens forming networks 6. Anchoring fibril collagens 7. Transmembrane collagens 8. Multiplex collagens |
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What is the most abundant type of collagen in the body?
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Fibril-forming collagens / Fibrillar
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What are the structural characteristics of Fibril-forming / Fibrillar collagens?
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- Right rod-like structure (right handed triple helix)
- Composed of 3 left handed alpha-chains - 3.6 AA/turn |
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What is the function of Fibril-forming / Fibrillar collagens?
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Give tissues tensile strength
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What are the major Fibril-forming / fibrillar collagen types?
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- Type I (major)
- Types III and V |
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What is the function of FACIT (Fibril-Associated Collagens w/ Interrupted Triple helices) collagens?
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Act as spacers between fibril collagen bundles and other ECM molecules
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What are the structural characteristics of FACIT (Fibril-Associated Collagens w/ Interrupted Triple helices) collagens?
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Some have glycosaminoglycans covalently attached (such as type IX)
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What are the structural characteristics of Collagen Type IV?
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- Microfibrillar collagens
- Similar to fibrillar collagens in that they form right handed triple helices and form dimers and tetramers, but do not form large fiber complexes |
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What is the function of Collagen Type IV?
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Form a network of collagen found in basement membranes
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What are the structural characteristics of beaded filament collagens?
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Form dimers and tetramers that are composed of helical structures
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What is an example of beaded filament collagens? Where are they found?
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- Collagen VI
- Found in most tissues |
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What are the functions of collagens forming networks?
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- Build structures including a hexagonal form
- Present in basement membranes |
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What are the functions of Anchoring Fibril Collagens?
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- Form filaments that are part of the anchor mechanism of cells to basement membranes
- E.g., collagen VII anchors the lamina densa to the dermis |
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What is the function of Transmembrane Collagens?
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Part of hemidesmosomes that attach epithelial cells to basement membranes
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What are the structural characteristics of Multiplex collagens?
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- Contain multiple triple helices interrupted by non-collagenous regions
- They can have glycosaminoglycans attached |
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What are the functions of Multiplex Collagens?
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Found in basement membranes and between collagen fibrils
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What kind of collagens are found in skin?
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- Fibrillar collagens: I, III, V, XI
- Facit collagens: XII, XIV, XVI, XX, XXI - Basement membrane collagen: IV - Microfibrillar collagen: VI - Anchoring fibril collagen: VII - Transmembrane collagen: XIII, XVII (BP180), XVII |
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What are the functions of the collagens in the skin?
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- Type XVII collagen is found in hemidesmosomes - connect basal keratinocytes to BM of dermis
- Collagens interact w/ other components of ECM such as fibrillin, elastin, fibronectin, and proteoglycans |
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What kind of collagens are found in bone?
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- Fibril-forming collagens: I and III
- Microfibrillar collagens: VI and XXIV in developing bone |
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What are the functions of the collagens in bone?
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Interact w/ proteoglycans and other glycoproteins in the ECM
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What kind of collagens are found in cartilage?
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- High amounts of fibril-forming collagens
- Type II collagen (most) - Also: Type XI and XXVII - Basement membrane: Type X and FACIT collagen type IX |
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What are the functions of the collagens in cartilage?
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Interact w/ proteoglycans in cartilage
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When does collagen synthesis occur?
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- Development and growth (slow turnover)
- Injury and restorative wound healing (rapid turnover) |
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What replaces collagens during wound healing?
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Fibroblasts
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What are the steps of general collagen synthesis and assembly?
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1. Procollagen translation
2. Hydroxylation 3. Glycosylation 4. Association of 3 procollagen chains 5. Disulfide bridge formation 6. Triple helix formation 7. Procollagen secretion 8. Propeptide cleavage 9. Fibril formation 10. Fibril cross-linking 11. Collagen fiber formation |
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What happens during the first step of collagen synthesis?
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Procollagen translation (1) - synthesized on ribosomes in ER that includes a signal peptide (which is cleaved by collagen signal peptidase), N & C terminal propeptides (necessary for proper fibril formation), and central helical region (becomes mature collagen molecule)
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What happens during the second step of collagen synthesis, after procollagen translation?
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Hydroxylation (2) - lysine and proline resis are hydroxylated; requires vitamin C cofactor (otherwise causes scurvy); hydroxylation induces a "pucker" that helps w/ formation of triple helix
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What happens during the third step of collagen synthesis, after hydroxylation?
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Glycosylation (3) - on 5-hydroxylysine residues w/ galactose transferase w/ UDP-galactose or glucose transferase w/ UDP-glucose
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What happens during the fourth step of collagen synthesis, after glycosylation?
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Association of 3 procollagen chains (4) - individual chains form left handed alpha-helix spontaneously by recognition of sequences in C-terminus
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What happens during the fifth step of collagen synthesis, after association of 3 procollagen chains?
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Disulfide bridge formation (5) - protein disulfide isomerase (PDI) makes cross-links between propeptides of 3 chains at C-termini
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What happens during the sixth step of collagen synthesis, after disulfide bridge formation?
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Triple helix formation (6) - form right handed triple helix from C --> N (must occur at proper time to prevent over or under hydroxylation or glycosylation which could cause unusual interactions and degradation)
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What happens during the seventh step of collagen synthesis, after triple helix formation?
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Procollagen secretion (7) - abnormal collagens and excess monomers and dimers degraded intracellularly
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What happens during the eighth step of collagen synthesis, after procollagen secretion?
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Propeptide Cleavage (8) - proteolysis of N and C termini by proteinases produces rod-like collagen (tropocollagen)
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What happens during the ninth step of collagen synthesis, after propeptide cleavage?
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Fibril formation (9) - tropocollagens associate in a staggered manner
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What happens during the tenth step of collagen synthesis, after fibril formation?
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Fibril cross-linking (10) - lysine residues at C-termini of staggered tropocollagens are oxidized by lysyl oxidase to form allysine (requires oxygen and copper); allysine residues form covalent cross-links w/ other allysine, lysine, or hydroxylysine resis
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What happens during the eleventh step of collagen synthesis, after fibril cross-linking?
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Collagen fiber formation (11) - collagen fibrils interact w/ FACT collagens and proteoglycans to regulate spacing of fibers w/in ECM
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What allows the corneal stroma to be a transparent tissue?
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- The hexagonal arrangement of fibril forming collagens and associated FACIT collagens and proteoglycans
- Most stromal proteoglycans that interact w/ fibril forming collagens are small consisting of only a core protein and covalently attached glycosaminoglycans |
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What interactions occur with laminin, a cross-shaped glycoprotein?
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- Type IV collagen - to basement membrane
- Integrins - to cells (integrins also bind to collagens, proteoglycans, and other ECM) - Specific laminin receptors - to cells - Proteoglycans and other proteins |
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What do proteoglycans interact with?
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Collagens, laminin, fibronectin, and elastin
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What is the structure of proteoglycans?
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Protein backbone w/ attached N and O linked glycosaminoglycans (especially keratin sulfate, chondroitin sulfate, heparin, heparin sulfate, and dermatan sulfate)
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What are the functions of proteoglycans?
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- Bind a large amount of water and various positively charged ions; important for proper hydration of tissue
- Contribute to spacing of collagen fibrils in tissues - Acts as a sieve - Facilitates cell migration |
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What is the major proteoglycan in cartilage? Function? Structure?
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"Aggrecan"
- Multiple aggrecan molecules bind to hyaluronan through N-termini and link proteins - Composed of core protein w/ chondroitin sulfate and keratin sulfate glycosaminoglycans covalently bound to usually serine residues (O-link) |
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What is fibronectin? Function?
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- Protein in many ECM
- Binds to fibril-forming collagens, fibrin, proteoglycans, and cells |
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What are the collagen associated diseases?
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- Ehlers Danlos Syndrome
- Osteogenesis Imperfecta - Alport Syndrome - Scurvy |
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What are the characteristic symptoms of Ehlers Danlos Syndrome?
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- Hyperextensible skin
- Fragile tissue - Overly mobile joints - Tissues easily bruised and heal poorly |
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What can cause Ehlers Danlos Syndrome?
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- Mutations in either collagen genes or enzymes that process collagen
- E.g., Mutations in genes for collagen types I, III, and V, lysyl hydroxylase, galactosyltransferase and procollagen N-proteinase - Also mutations in enzymes involved in proteoglycan synthesis (e.g., dermatan-4-sulfotransferase) |
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What are the characteristic symptoms of Osteogenesis Imperfecta?
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- Brittle, bowed bones w/ frequent fractures
- Abnormal bleeding - Blue scleras - Hearing loss - Poor tooth development |
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What can cause Osteogenesis Imperfecta?
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- Mutations in type I collagens --> over hydroxylation and over glycosylation of collagen molecules --> abnormal triple helix formation and intracellular degradation
- Glycine resis --> bulky side chain alters formation of triple helix - Or mutations in other collagens (VII and VIII) rarely or other moelcules important for fibril formation (prolyl-3-hydroxylase and chaperone proteins) |
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What are the characteristic symptoms of Alport Syndrome?
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- Hematuria
- Progressive renal damage - Hearing loss - Ocular deficits |
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What can cause Alport Syndrome?
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Mutations in Type IV collagen resulting in abnormal formation of collagens in BMs
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What are the characteristic symptoms of Scurvy?
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- Easy bruising and poor wound healing
- Bleeding gums - Subcutaneous hemorrhages - Teeth can become loose - Scar tissue can rupture - Corkscrew hairs |
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What can cause Scurvy?
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Deficiency of hydroxylation reaction cofactor Vitamin C (ascorbate) --> reduced hydroxylation of collagen by lysyl and prolyl hydroxylases --> triple helix is incorrectly formed --> degradation of collagen
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