collagen 4 alpha-3; Goodpasture antigen; contains: tumstatin (COL4A3)

Function

• type 4 collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans & entactin/nidogen
• tumstatin, a cleavage fragment corresponding to the NC1 domain
  • has both anti-angiogenic & anti-tumor cell activity
    • these two activities may be regulated via RGD-independent ITGB3-mediated mechanisms
• Pro at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains
• isoform 2 contains an additional N-linked glycosylation site
• type 4 collagen contains numerous Cys which are involved in intermolecular & intramolecular disulfide bonding
  • 12 of these, located in the NC1 domain, are conserved in all known type 4 collagen
• the trimeric structure of the NC1 domains is stabilized by covalent bonds between Lys & Met residues (putative)
• phosphorylated by the Goodpasture antigen-binding protein (COL4A3BP)
• there are six type 4 collagen isoforms, each of which can form a triple helix structure with 2 other chains to generate type 4 collagen network
• forms a triple helical protomer with collagen 4 alpha-4 & collagen 4 alpha-5
  • this triple helical structure dimerizes through NC1-NC1 domain interactions such that the COL4A3, COL4A4 & COL4A5 of one protomer connect with the COL4A5, COL4A4 & COL4A3 of the opposite protomer, respectively
• interacts with COL4A3BP & ITGB3
• associates with LAMB2 at the neuromuscular junction & in GBM (putative)

Structure

• alpha chains of type 4 collagen have
  • a non-collagenous domain (NC1) at their C-terminus
  • frequent interruptions of the G-X-Y repeats in the long central triple-helical domain (which may cause flexibility in the triple helix)
  • a short N-terminal triple-helical 7S domain
• belongs to the type 4 collagen family
• contains 1 collagen 4 NC1 (C-terminal non-collagenous) domain

Compartment

• secreted, extracellular space
• extracellular matrix, basement membrane
• colocalizes with COL4A4 & COL4A5 in GBM, tubular basement membrane & synaptic basal lamina (putative)

Alternative splicing

• named isoforms=5
• the majority of isoforms differ in the C-terminal part of the NC1 domain

Expression

• collagen 4 alpha-3 & collagen 4 alpha-4 are colocalized & present in kidney, eye, basement membranes of lens capsule, cochlea, lung, skeletal muscle, aorta, synaptic fibers, fetal kidney & fetal lung
• isoform 1 & isoform 3 are strongly expressed in kidney, lung, suprarenal capsule, muscle & spleen
  • in each of these tissues. isoform 1 is more abundant than isoform 3
• isoform 1 & isoform 3 are expressed at low levels in artery, fat, pericardium & peripherical nerve
• isoform 1 & isoform 3 are not expressed in placenta, mesangium, skin, pleura & cultured umbilical endothelial cells

Pathology

• autoantibodies in Goodpasture's syndrome
  • the epitopes recognized by the Goodpasture auto-antibodies are sequestered within the NC1 hexamer of type 4 collagen
• defects in COL4A3 are associated with
  • hereditary nephritis
  • thin glomerular basement membrane disease
• mutations in Alport syndrome
  • autosomal dominant
  • autosomal recessive
• defects in COL4A3 are a cause of benign familial hematuria

More general terms

• collagen subunit
• phosphoprotein

Component of

• collagen type-4

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1285
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1285
• OMIM: https://mirror.omim.org/entry/104200
• OMIM: https://mirror.omim.org/entry/120070
• OMIM: https://mirror.omim.org/entry/141200
• OMIM: https://mirror.omim.org/entry/203780
• UniProt: http://www.uniprot.org/uniprot/Q01955.html