Collagen, type IV, alpha 1

Last updated
COL4A1
Protein COL4A1 PDB 1li1.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases COL4A1 , HANAC, ICH, POREN1, arresten, BSVD, RATOR, collagen type IV alpha 1, collagen type IV alpha 1 chain, BSVD1, PADMAL, COL4A1s
External IDs OMIM: 120130; MGI: 88454; HomoloGene: 20437; GeneCards: COL4A1; OMA:COL4A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001845
NM_001303110

NM_009931

RefSeq (protein)

NP_001290039
NP_001836

NP_034061

Location (UCSC) Chr 13: 110.15 – 110.31 Mb Chr 8: 11.25 – 11.36 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. [5] [6] It is ubiquitously expressed in many tissues and cell types. [7] COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. [8] Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. [9] [10] [11] [12] The COL4A1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [13]

Contents

Structure

Gene

The COL4A1 gene resides on chromosome 13 at the band 13q34 and contains 54 exons.[5] This gene produces 2 isoforms through alternative splicing. [14]

Protein

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. [14] [15] The triple-helical domain contains interrupted G-X-Y repeats, which is suspected to allow flexibility of the domain. [14] 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. [15]

Function

Type IV collagen is the major structural component of basement membranes, which contains two or three COL4A1 proteins. [9] Thus, COL4A1 is abundant and found in all types of basement membranes. [10] The NC1 domain of COL4A1 is an important antiangiogenic molecule to control the formation of new capillaries. [16] 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. [17]

Clinical significance

Mutations in COL4A1 exons 24 and 25 are associated with HANAC (autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps). [18] It has also been confirmed that mutations in the COL4A1 gene occur in some patients with porencephaly and schizencephaly. [19] [20]

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. [11] 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. [11]

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. [12] Altogether, it was concluded that the pathogenesis of coronary artery disease may be regulated by COL4A1 and COL4A2 genes. [12]

An autosomal recessive encephalopathy associated with mutations in this gene has also been reported. [21]

Clinical Marker

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). [13]

Related Research Articles

<span class="mw-page-title-main">Alport syndrome</span> Medical condition

Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.

<span class="mw-page-title-main">Laminin</span> Protein in the extracellular matrix

Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina. Laminins are vital to biological activity, influencing cell differentiation, migration, and adhesion.

<span class="mw-page-title-main">Collagen, type I, alpha 1</span> Mammalian protein found in humans

Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the COL1A1 gene. COL1A1 encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including cartilage.

<span class="mw-page-title-main">Collagen, type XI, alpha 2</span> Protein found in humans

Collagen alpha-2(XI) chain is a protein that in humans is encoded by the COL11A2 gene.

<span class="mw-page-title-main">Collagen, type III, alpha 1</span>

Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded by the COL3A1 gene. Type III collagen is one of the fibrillar collagens whose proteins have a long, inflexible, triple-helical domain.

Collagen IV is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, collagen IV lacks the regular glycine in every third residue necessary for the tight, collagen helix. This makes the overall arrangement more sloppy with kinks. These two features cause the collagen to form in a sheet, the form of the basal lamina. Collagen IV is the more common usage, as opposed to the older terminology of "type-IV collagen". Collagen IV exists in all metazoan phyla, to whom they served as an evolutionary stepping stone to multicellularity.

<span class="mw-page-title-main">Collagen, type VII, alpha 1</span> Protein found in humans

Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene. It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane. Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype. It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.

<span class="mw-page-title-main">Collagen, type IV, alpha 5</span> Protein-coding gene in humans

Collagen alpha-5(IV) chain is a protein that in humans is encoded by the COL4A5 gene.

<span class="mw-page-title-main">Collagen, type IV, alpha 3</span> Protein found in humans

Collagen alpha-3(IV) chain is a protein that in humans is encoded by the COL4A3 gene.

<span class="mw-page-title-main">Collagen, type IV, alpha 4</span> Protein found in humans

Collagen alpha-4(IV) chain is a protein that in humans is encoded by the COL4A4 gene.

<span class="mw-page-title-main">Laminin, alpha 5</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-5 is a protein that in humans is encoded by the LAMA5 gene.

<span class="mw-page-title-main">Collagen, type IV, alpha 2</span>

Collagen alpha-2(IV) chain is a protein that in humans is encoded by the COL4A2 gene.

<span class="mw-page-title-main">Laminin subunit gamma-2</span> Protein-coding gene in the species Homo sapiens

Laminin subunit gamma-2 is a protein that in humans is encoded by the LAMC2 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 1</span> Protein found in humans

Collagen alpha-1(VI) chain is a protein that in humans is encoded by the COL6A1 gene.

<span class="mw-page-title-main">Collagen, type X, alpha 1</span> Protein found in humans

Collagen alpha-1(X) chain is a protein that in humans is a member of the collagen family encoded by the COL10A1 gene.

<span class="mw-page-title-main">Laminin subunit alpha-2</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-2 is a protein that in humans is encoded by the LAMA2 gene.

<span class="mw-page-title-main">Collagen, type IV, alpha 6</span> Mammalian protein found in humans

Collagen alpha-6(IV) chain is a protein that in humans is encoded by the COL4A6 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 2</span> Protein found in humans

Collagen alpha-2(VI) chain is a protein that in humans is encoded by the COL6A2 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 3</span> Mammalian protein found in humans

Collagen alpha-3(VI) chain is a protein that in humans is encoded by the COL6A3 gene. This protein is an alpha chain of type VI collagen that aids in microfibril formation. As part of type VI collagen, this protein has been implicated in Bethlem myopathy, Ullrich congenital muscular dystrophy (UCMD), and other diseases related to muscle and connective tissue.

<span class="mw-page-title-main">Collagen, type VIII, alpha 1</span> Protein found in humans

Collagen alpha-1(VIII) chain is a protein that in humans is encoded by the COL8A1 gene.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031502 Ensembl, May 2017
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  21. Yaramis A, Lochmüller H, Töpf A, Sonmezler E, Yilmaz E, Hiz S, Yis U, Gungor S, Ipek Polat A, Edem P, Beltran S, Laurie S, Yaramis A, Horvath R, Oktay Y (2020) COL4A1-related autosomal recessive encephalopathy in 2 Turkish children. Neurol Genet 6(1):e392

Further reading