collagen and basement membranes

what is the most abundant protein in the body

• collagen

• 80% is collagen 1

structure of collagen

• 3 polypeptide chains triple helix

• repeating sequence Gly-X-Y

• tight wrapping due to proline

• glycine adds flexibility

hydrogen bonding between adjacent collagen fibres

• hydroxylation of proline and lysine

• lysine hydroxylase and proline hydroxylase 

• require vitamin C as a cofactor 

lysil oxidase

• deaminates hydroxylyisne and lysine

• generates reactive aldehyde groups

• forms covalent bonds with other lysine and hydroxylysines 

what is the first extracellular matrix to form during metazoan development

basement membrane

collagen iv structure

• N terminal 7s domain, cys/lys rich allows crosslinking of triple helices via disulfide and lysine hydroxylysine crosslinks

• gly-x-y repeats have interruptions in collagen IV - inc flexibility for crosslinking

• c terminal NC1, drive triple helix formation, hexamer formation via end end interactions

making collagen iv trimer

• pro alpha chains are synthesised in ribosome

• hydroxylation of selected prolines and lysines

• self assembly of three pro alpha chains

• groove of nc1 terminal allows interactions to form hexamer

• 7s domains interact to form a tetramer of collagen

three possible heterotrimers that can be expressed

• alpha 1 alpha 1 alpha 2

• alpha 3 alpha 4 alpha 5

• alpha 5 alpha 5 alpha 6

heterotrimer in GBM

• alpha 3 alpha 4 alpha 5

alports syndrome 

• loss of a3a4a5 in GBM → a1a2a1

• delamination of the GBM

• results in kideny disease

• due to mutation of COL4A5 X linked gene

structural impact of a3a4a5

• more inter and intra chain crosslinks

• protects from inc pressure

• protects from proteolysis from proteases

knock out GM mouse alports

COL4A3 knockout in mice develop progressive glomerulopathy

• this phenocopies human autosomal dominant Alports

• mouse dies XD

treatment for alports syndrome

• ACE inhibitors (pril)

• block angiotensin i to angiotensin i

• reduce blood pressure, reduce pressure of glomerulus, inc life span

• if functional copy is gained, GBM can be repaired

how do collagen fibrils and GAGs contrast

• collagen fibrils resist tensile forces

• while GAGs resist compressive forces

GAGs glycosaminoglycans

• highly charged polysaccharides

• repeated disaccharide units

• fill most of the extracellular space

• high density of neg charge attracts anionslike Na+ - allows water to be sucked into the matrix

• resist compressive forces

proteoglycans

• GAGs covalently linked to core proteins

• form ground substance in connective tissue