Overview 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