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Synthesis and Structure
  •  Inside fibroblasts
    • pre-pro-collagen α chain formation
      • RER-bound ribosomes synthesize
      • contains hydrophobic translocation sequence
      • chain formed mainly of repeating tripeptide
        • Gly-X-Y
          • X and Y are proline, lysine
    • pro-collagen α chain formation
      • hydrophobic sequence cleaved
    • hydroxylated pro-collagen α chain formation
      • X and Y position prolines and lysines are hydroxylated to form hydroxylysine and hydroxyproline.
        • these amino acids are unique to collagen
        • hydroxylated as peptide chain passes into ER
        • performed by prolyl and lysyl hydroxylase
        • lack of lysyl hydroxylase function results in weak collagen chains
          • requires ascorbic acid (Vitamin C)
            • lack of vitamin C causes scurvy
              • presentation
                • swollen gums, bruising, anemia, poor wound healing
          • can also be caused by defective lysyl hydroxylase gene
            • Ehlers-Danlos syndrome
              • nine different types
              • lysyl hydroxylase gene deficiency is one of many causes
              • presentation
                • hyperextensible skin, hyperflexible joints, weak vessel walls (↑ risk for aneurysm)
    • glycosylated pro-collagen α chain formation
      • hydroxylysines are glycosylated
    • pro-collagen α chain trimer formation
      • three α chains associate
      • moved from RER to Golgi
      • secreted out of the fibroblast
  • Outside fibroblasts
    • collagen molecule (tropocollagen) formation
      • propeptides cleaved from ends and becomes insoluble
      • presence of propeptide does not allow assembly intracellularly
    • collagen fibril formation
      • catalyzed by lysyl oxidase
        • covalently links α chains by crosslinking hydroxylysines
        • copper required as cofactor
          • lack of copper results from Menke’s disease
            • at low serum concentrations of copper this enzyme cannot function and weak collagen is formed
            • cause
              • X-linked gene mutation in ATP7A
                • ATP-dependent copper efflux protein
              • aka Ehlers-Danlos syndrome type IX
              • inability of enterocytes to release absorbed copper
              • copper at toxic levels in small intestine and kidneys
              • copper in circulation and in brain at low levels
            • presentation
              • presents like a copper deficiency
              • seizures, failure to thrive, neurodegeneration
              • steel-colored and brittle hair
    • collagen fiber formation
      • fibrils aggregate to form final bundles of triple helix quaternary protein structure

 

Collagen Types
  • Type I
    • thick, rope-like bundles of collagen
      • strongest tensile form of collagen
    • majority of collagen in the body (approx. 90%)
    • found in locations where high tensile strength is needed
      • bone, fascia, tendons, teeth (dentin), cornea, skin
      • type III of early wound repair converted to type I in late wound repair 
    • defective in osteogenesis imperfecta (OI) type I  
      • aka brittle bone disease
      • AD, in most cases
      • presentation
        • multiple fractures with minimal force
          • first fractures may occur during delivery
        • blue sclerae
          • due to the translucency of the connective tissue over the choroid due to lack of collagen
        • deafness (50%)
          • abnormal middle ear bones
        • dental abnormalities
      • may be confused with child abuse
    • defective in various forms of Ehlers-Danlos syndrome
      • faulty collagen synthesis
      • see above
  • Type II
    • spongy collagen to absorb shock
    • found in tissues where there are compression forces
      • cartilage (including hyaline), vitreous body of the eye, nucleus pulposus of vertebral disc
  • Type III
    • web-like fibers where forces pull from many directions
      • aka reticulin
    • found in tissues where strength is needed (but not compression or tensile)
      • skin, blood vessels, uterus, fetal tissue
      • granulation tissue
        • type III of early wound repair converted to type I in late wound repair
    • defective in Ehlers-Danlos type IV
      • faulty collagen synthesis
      • associated with
        • joint dislocation
        • berry aneurysms
        • organ rupture
      • see above
  • Type IV
    • basement membrane
      • especially kidney, ears, eyes, skin
    • organizes/solidifies cellular structure
    • defective in Alport's syndrome
      • effects the tissues where type IV is most prominent
        • kidney → progressive hereditary nephritis
        • ears → deafness
        • eyes → ocular disturbances
      • majority of cases are X-linked dominant
    • one of the causes of epidermolysis bullosa
      • weak union of dermis and epidermis of the skin
      • easily formed blisters
    • Goodpasture's syndrome involves an auto-antibody against collagen type IV in pulmonary and glomerular capillaries
      • presents with hemoptysis and glomerular disease
 

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