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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 [5]
- mutations in Alport syndrome
- autosomal dominant
- autosomal recessive
- defects in COL4A3 are a cause of benign familial hematuria
Related
COL4A3 gene
General
collagen subunit
phosphoprotein
Properties
SIZE: entity length = 1670 aa
MW = 162 kD
MOTIF: signal sequence {1-28}
7S {29-42}
Triple-helical region {43-1438}
MOTIF: N-glycosylation site {N253}
Cell attachment {791-793}
Cell attachment {996-998}
Cell attachment {1154-1156}
Cell attachment {1306-1308}
Cell attachment {1345-1347}
proteolytic site {1426-1427}
Goodpasture epitope {1427-1444}
MOTIF: Cell attachment {1432-1434}
Ser phosphorylation site {S1435}
Ser phosphorylation site {S1437}
Collagen IV NC1 {1445-1669}
MOTIF: cysteine residue {C1460}
MODIFICATION: cysteine residue {C1551}
anti-angiogenic {1479-1557}
cysteine residue {C1493}
MODIFICATION: cysteine residue {C1548}
cysteine residue {C1505}
MODIFICATION: cysteine residue {C1511}
cysteine residue {C1511}
MODIFICATION: cysteine residue {C1505}
cysteine residue {C1548}
MODIFICATION: cysteine residue {C1493}
cysteine residue {C1551}
MODIFICATION: cysteine residue {C1460}
cysteine residue {C1570}
MODIFICATION: cysteine residue {C1665}
cysteine residue {C1604}
MODIFICATION: cysteine residue {C1662}
anti-tumor cell {1610-1628}
cysteine residue {C1616}
MODIFICATION: cysteine residue {C1622}
cysteine residue {C1622}
MODIFICATION: cysteine residue {C1616}
cysteine residue {C1662}
MODIFICATION: cysteine residue {C1604}
cysteine residue {C1665}
MODIFICATION: cysteine residue {C1570}
Database Correlations
OMIM correlations
UniProt Q01955
PFAM correlations
Entrez Gene 1285
Kegg hsa:1285
References
- UniProt :accession Q01955
- GeneReviews
http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/COL4A3
- OMIM :accession 120070
- Entrez Gene :accession 1285
- Medical Knowledge Self Assessment Program (MKSAP) 17,
American College of Physicians, Philadelphia 2015