Collagen, type III, alpha 1

COL3A1
Gene ontology
Molecular function	metal ion binding integrin binding protein binding platelet-derived growth factor binding SMAD binding extracellular matrix structural constituent protease binding extracellular matrix structural constituent conferring tensile strength
Cellular component	collagen endoplasmic reticulum lumen extracellular space collagen type III trimer extracellular matrix extracellular region collagen-containing extracellular matrix
Biological process	positive regulation of Rho protein signal transduction skeletal system development negative regulation of neuron migration response to cytokine response to mechanical stimulus human ageing extracellular matrix organization platelet activation heart development peptide cross-linking negative regulation of immune response blood vessel development regulation of immune response cerebral cortex development collagen catabolic process cellular response to amino acid stimulus integrin-mediated signaling pathway response to radiation cell-matrix adhesion digestive tract development transforming growth factor beta receptor signaling pathway aorta smooth muscle tissue morphogenesis skin development collagen fibril organization wound healing supramolecular fiber organization
Sources:Amigo / QuickGO

Ensembl				ENSG00000168542	ENSMUSG00000026043
UniProt	P02461	P08121
RefSeq (mRNA)	NM_000090 NM_001376916	NM_009930
RefSeq (protein)	NP_000081	NP_034060
Location (UCSC)	Chr 2: 188.97 – 189.01 Mb	Chr 1: 45.35 – 45.39 Mb
PubMed search	[3]	[4]

Wikidata

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Type III Collagen is a homotrimer, or a protein composed of three identical

Protein structure and function

Type III collagen is synthesized by cells as a pre-procollagen.[6]

The

. In addition, crosslinks form between certain lysine and hydroxylysine residues. In the extracellular space in tissues, type III collagen monomers assemble into macromolecular fibrils, which aggregate into fibers, providing a strong support structure for tissues requiring tensile strength.

The triple-helical conformation, which is a characteristic feature of all fibrillar collagens, is possible because of the presence of a glycine as every third amino acid in the sequence of about 1000 amino acids. When the right-handed super-helix is formed, the glycine residues of each of the monomers is positioned at the center of the super-helix (where the three monomers "touch"). Each left-handed helix is characterized by a complete turn in about 3.3 amino acids. The periodicity induced by the glycines at non-integer spacing results in a super-helix that completes one turn in about 20 amino acids. This (Gly-X-Y)n sequence is repeated 343 times in the type III collagen molecule. Proline or hydroxyproline is often found in the X- and Y-position giving the triple helix stability.

In addition to being an integral structural component of many organs, type III collagen is also an important regulator of the diameter of type I and II collagen fibrils. Type III collagen is also known to facilitate platelet aggregation through its binding to platelets and therefore, play an important role in blood clotting.

Tissue distribution

Type III collagen is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. It is also found in many other tissues together with type I collagen.

Gene

The COL3A1 gene is located on the long (q) arm of chromosome 2 at 2q32.2, between positions 188974372 and 189012745. The gene has 51 exons and is approximately 40 kbp long.^[7] The COL3A1 gene is in tail-to-tail orientation with a gene for another fibrillar collagen, namely COL5A2.^[7]

Two transcripts are generated from the gene using different polyadenylation sites.

Clinical significance

Mutations in the COL3A1 gene cause

A few patients with arterial aneurysms without clear signs of EDS have also been found to have COL3A1 mutations.[13]^[14][15]

More recently, mutations in COL3A1 have also been identified in patients with severe brain anomalies suggesting that type III collagen is important for the normal development of the brain during embryogenesis.^{[16][17][18][19]} This disease is similar to that caused by mutations in GRP56 (OMIM 606854). Type III collagen is a known ligand for the receptor GRP56.

The first single base mutation in the COL3A1 gene was reported in 1989 in a patient with vEDS and changed a glycine amino acid to a serine

, in which the Gly-Xaa-Yaa triplets stay in frame and there are no premature termination codons.

The functional consequences of COL3A1 mutations can be studied in a cell culture system. A small bunch biopsy of skin is obtained from the patient and used to start the culture of skin fibroblasts which express type III collagen.^[13] The type III collagen protein synthesized by these cells can be studied for its thermal stability. In other words, the collagens can be subjected to a short digestion by proteinases called trypsin and chymotrypsin at increasing temperatures. Intact type III collagen molecules, which have formed a stable triple helix, can withstand such treatment till about 41oC, whereas molecules with mutations that lead to glycine substitutions fall apart at a much lower temperature.

It is difficult to predict the clinical severity based on the type and location of COL3A1 mutations.^[22][23] Another important clinical implication is that several studies have reported on mosaicism.^[12][24] This refers to a situation where one of the parents carries the mutation in some, but not all of her or his cells, and appears phenotypically healthy, but has more than one affected offspring. In such a situation the risk for another affected child is higher than in a genotypically normal parent.^[25]

Type III collagen could also be important in several other human diseases. Increased amounts of type III collagen are found in many fibrotic conditions such as liver and kidney fibrosis, and systemic sclerosis.^{[26][27][28][29][30][31]} This has led to a search for serum biomarkers that could be used for diagnosing these conditions without having to obtain a tissue biopsy. The most widely used biomarker is the N-terminal propeptide of type III procollagen, which is cleaved off during the biosynthesis of type III collagen.^[32]

Animal models

Four different mouse models with COL3A1 defects have been reported.^{[33][34][35][36]} Inactivation of the murine COL3A1 gene using homologous recombination technique led to a shorter life span in homozygous mutant mice. The mice died prematurely from a rupture of major arteries mimicking the human vEDS phenotype. These mice also had a severe malformation of the brain. Another study discovered mice with a naturally occurring large deletion of the COL3A1 gene. These mice died suddenly due to thoracic aortic dissections. The third type of mutant mice were transgenic mice with a Gly182Ser mutation. These mice developed severe skin wounds, demonstrated vascular fragility in the form of reduced tensile strength and died prematurely at the age of 13–14 weeks. The fourth mouse model with defective COL3A1 gene is the tight skin mouse (Tsk2/+), which resembles the human systemic sclerosis.

See also

• Collagen
• Ehlers-Danlos syndrome

Notes

Wikidata Q65950306 .

References

Further reading

• Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. (March 2017). "The 2017 international classification of the Ehlers-Danlos syndromes". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 175 (1): 8–26.
  PMID 28306229
  .
• Malfait F (October 2018). "Vascular aspects of the Ehlers-Danlos Syndromes". Matrix Biology. 71–72: 380–395.
  S2CID 13705584
  .
• Kuivaniemi H, Tromp G, Prockop DJ (November 1991). "Genetic causes of aortic aneurysms. Unlearning at least part of what the textbooks say". The Journal of Clinical Investigation. 88 (5): 1441–4.
  PMID 1939638
  .
• Kuivaniemi H, Tromp G, Prockop DJ (1997). "Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels". Human Mutation. 9 (4): 300–15.
  S2CID 6890740
  .
• Kuivaniemi H, Tromp G, Prockop DJ (April 1991). "Mutations in collagen genes: causes of rare and some common diseases in humans". FASEB Journal. 5 (7): 2052–60.
  S2CID 24461341
  .
• Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N (March 2017). "Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 175 (1): 40–47.
  PMID 28306228
  .
• Boudko SP, Engel J, Okuyama K, Mizuno K, Bächinger HP, Schumacher MA (November 2008). "Crystal structure of human type III collagen Gly991-Gly1032 cystine knot-containing peptide shows both 7/2 and 10/3 triple helical symmetries". The Journal of Biological Chemistry. 283 (47): 32580–9.
  PMID 18805790
  .
• Lamberg A, Helaakoski T, Myllyharju J, Peltonen S, Notbohm H, Pihlajaniemi T, Kivirikko KI (May 1996). "Characterization of human type III collagen expressed in a baculovirus system. Production of a protein with a stable triple helix requires coexpression with the two types of recombinant prolyl 4-hydroxylase subunit". The Journal of Biological Chemistry. 271 (20): 11988–95.
  PMID 8662631
  .

External links

• Collagen+type+III at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• "COL3A1". Ehlers Danlos Syndrome Variant Database. Archived from the original on 2021-01-26. Retrieved 2018-12-05.
• "Report for CCDS2297.1". Consensus Coding Sequence (CDS) Database. National Center for Biotechnology Information (NCBI).
• Byers PH, Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (1993). "Vascular Ehlers-Danlos Syndrome". Ehlers-Danlos Syndrome Type IV. NCBI/NIH/UW.
  PMID 20301667. {{cite book}}: |work= ignored (help
  )