COL4A1 belongs to the type IV collagen family and contains three domains: a short N-terminal domain, a long triple-helical 7S domain at its center, and a non-collagenous 1 (NC1) domain at its C-terminal. The triple-helical domain contains interrupted G-X-Y repeats, which is suspected to allow flexibility of the domain. The NC1 domain is composed of two trimeric caps, each containing two alpha 1 fragments and one alpha 2 fragment, that form a sixfold propeller arranged around an axial tunnel. The interaction between these two caps occurs along a large planar interface and is stabilized by a covalent cross-link between the alpha 1 and alpha 2 chains across the two caps.
Type IV collagen is the major structural component of basement membranes, which contains two or three COL4A1 proteins. Thus, COL4A1 is abundant and found in all types of basement membranes. The NC1 domain of COL4A1 is an important antiangiogenic molecule to control the formation of new capillaries. NC1 binds to the α1β1 integrin and inhibits specific integrin signaling pathways in vascular epithelial cells. It also regulates HIF-1α and VEGF expression, presumably by inhibiting the MAPK signaling cascade. These findings may explain the antitumorigenic function of NC1.
In humans, a novel mutation of the COL4A1 gene coding for collagen type IV was found to be associated with autosomal dominant congenital cataract in a Chinese family. This mutation was not found in unaffected family members or in 200 unrelated controls. In this study, sequence analysis confirmed that the Gly782 amino acid residue was highly conserved. This report of a new mutation in the COL4A1 gene is the first report of a non-syndromic autosomal dominant congenital cataract that highlights an important role for collagen type IV in the physiological and optical properties of the lens.
Additionally, in the cardiovascular field, the COL4A1 and COL4A2 regions on chromosome 13q34 are a highly replicated locus for coronary artery disease. In a normal wall of arteries, collagen type IV acts to inhibit smooth muscle cell proliferation. Accordingly, it was demonstrated that protein expression of collagen type IV in human vascular smooth muscle cells is regulated by both SMAD3 protein and TGFβ mediated stimulation of mRNA. Altogether, it was concluded that the pathogenesis of coronary artery disease may be regulated by COL4A1 and COL4A2 genes.
A multi-locus genetic risk score study based on a combination of 27 loci, including the COL4A1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
↑Soininen R, Haka-Risku T, Prockop DJ, Tryggvason K (December 1987). "Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen". FEBS Letters. 225 (1–2): 188–94. doi:10.1016/0014-5793(87)81155-9. PMID3691802.
↑Maragoudakis ME, Missirlis E, Karakiulakis GD, Sarmonica M, Bastakis M, Tsopanoglou N (January 1993). "Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with anti-tumor properties". Kidney International. 43 (1): 147–50. doi:10.1038/ki.1993.24. PMID7679456.
↑Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P (December 2007). "COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps". The New England Journal of Medicine. 357 (26): 2687–95. doi:10.1056/NEJMoa071906. PMID18160688.
↑Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, Kakita A, Yamamoto T, Otsuki Y, Shimizu S, Wada T, Koyama N, Mino Y, Kondo N, Takahashi S, Hirabayashi S, Takanashi J, Okumura A, Kumagai T, Hirai S, Nabetani M, Saitoh S, Hattori A, Yamasaki M, Kumakura A, Sugo Y, Nishiyama K, Miyatake S, Tsurusaki Y, Doi H, Miyake N, Matsumoto N, Saitsu H (January 2013). "Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly". Annals of Neurology. 73 (1): 48–57. doi:10.1002/ana.23736. PMID23225343.
↑Smigiel R, Cabala M, Jakubiak A, Kodera H, Sasiadek MJ, Matsumoto N, Sasiadek MM, Saitsu H (April 2016). "Novel COL4A1 mutation in an infant with severe dysmorphic syndrome with schizencephaly, periventricular calcifications, and cataract resembling congenital infection". Birth Defects Research. Part A, Clinical and Molecular Teratology. 106 (4): 304–7. doi:10.1002/bdra.23488. PMID26879631.
Hinek A (July 1994). "Nature and the multiple functions of the 67-kD elastin-/laminin binding protein". Cell Adhesion and Communication. 2 (3): 185–93. doi:10.3109/15419069409004436. PMID7827955.
Ständer M, Naumann U, Wick W, Weller M (May 1999). "Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth". Cell and Tissue Research. 296 (2): 221–7. doi:10.1007/s004410051283. PMID10382266.
Ghebrehiwet B, Peerschke EI, Hong Y, Munoz P, Gorevic PD (June 1992). "Short amino acid sequences derived from C1q receptor (C1q-R) show homology with the alpha chains of fibronectin and vitronectin receptors and collagen type IV". Journal of Leukocyte Biology. 51 (6): 546–56. PMID1377218.
Gupta S, Batchu RB, Datta K (October 1991). "Purification, partial characterization of rat kidney hyaluronic acid binding protein and its localization on the cell surface". European Journal of Cell Biology. 56 (1): 58–67. PMID1724753.
Paralkar VM, Nandedkar AK, Pointer RH, Kleinman HK, Reddi AH (October 1990). "Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen". The Journal of Biological Chemistry. 265 (28): 17281–4. PMID2211625.
Aumailley M, Wiedemann H, Mann K, Timpl R (September 1989). "Binding of nidogen and the laminin-nidogen complex to basement membrane collagen type IV". European Journal of Biochemistry / FEBS. 184 (1): 241–8. doi:10.1111/j.1432-1033.1989.tb15013.x. PMID2506015.
Pihlajaniemi T, Tryggvason K, Myers JC, Kurkinen M, Lebo R, Cheung MC, Prockop DJ, Boyd CD (June 1985). "cDNA clones coding for the pro-alpha1(IV) chain of human type IV procollagen reveal an unusual homology of amino acid sequences in two halves of the carboxyl-terminal domain". The Journal of Biological Chemistry. 260 (12): 7681–7. PMID2581969.
Soininen R, Huotari M, Ganguly A, Prockop DJ, Tryggvason K (August 1989). "Structural organization of the gene for the alpha 1 chain of human type IV collagen". The Journal of Biological Chemistry. 264 (23): 13565–71. PMID2701944.
Siebold B, Deutzmann R, Kühn K (October 1988). "The arrangement of intra- and intermolecular disulfide bonds in the carboxyterminal, non-collagenous aggregation and cross-linking domain of basement-membrane type IV collagen". European Journal of Biochemistry / FEBS. 176 (3): 617–24. doi:10.1111/j.1432-1033.1988.tb14321.x. PMID2844531.
Bowcock AM, Hebert JM, Christiano AM, Wijsman E, Cavalli-Sforza LL, Boyd CD (1988). "The pro alpha 1 (IV) collagen gene is linked to the D13S3 locus at the distal end of human chromosome 13q". Cytogenetics and Cell Genetics. 45 (3–4): 234–6. doi:10.1159/000132460. PMID2891465.
Soininen R, Huotari M, Hostikka SL, Prockop DJ, Tryggvason K (November 1988). "The structural genes for alpha 1 and alpha 2 chains of human type IV collagen are divergently encoded on opposite DNA strands and have an overlapping promoter region". The Journal of Biological Chemistry. 263 (33): 17217–20. PMID3182844.
Brazel D, Oberbäumer I, Dieringer H, Babel W, Glanville RW, Deutzmann R, Kühn K (November 1987). "Completion of the amino acid sequence of the alpha 1 chain of human basement membrane collagen (type IV) reveals 21 non-triplet interruptions located within the collagenous domain". European Journal of Biochemistry / FEBS. 168 (3): 529–36. doi:10.1111/j.1432-1033.1987.tb13450.x. PMID3311751.