Collagen

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 Menkes 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 in severe form caused by collagen mutation
        • fractures will be milder and occur later in childhood with collagen deletion
      • 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