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. [5]
Type III collagen is synthesized by cells as a pre-procollagen. [6]
The signal peptide is cleaved off producing a procollagen molecule. Three identical type III procollagen chains come together at the carboxy-terminal ends, and the structure is stabilized by the formation of disulphide bonds. Each individual chain folds into left-handed helix and the three chains are then wrapped together into a right-handed superhelix, the triple helix. Prior to assembling the super-helix, each monomer is subjected to a number of post-translational modifications that occur while the monomer is being translated. First, on the order of 145 prolyl residues of the 239 in the triple-helical domain are hydroxylated to 4-hydroxyproline by prolyl-4-hydroxylase. Second, some of the lysine residues are hydroxylated or glycosylated, and some lysine as well as hydroxylysine residues undergo oxidative deamination catalysed by lysyl oxidase. Other post-translational modifications occur after the triple helix is formed. The large globular domains from both ends of the molecule are removed by C- and amino(N)-terminal-proteinases to generate triple-helical type III collagen monomers called tropocollagen. 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.
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.
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. [8] Although alternatively spliced transcripts have been detected for this gene, they are the result of mutations; these mutations alter RNA splicing, often leading to the exclusion of an exon or use of cryptic splice sites. [9] [10] [11] The resulting defective protein is the cause of a severe, rare disease, the vascular type of Ehlers-Danlos syndrome (vEDS). These studies have also provided important information about RNA splicing mechanisms in multi-exon genes. [11] [9]
Mutations in the COL3A1 gene cause Ehlers-Danlos syndrome, vascular type (vEDS; also known as the EDS type IV; OMIM 130050). It is the most severe form of EDS, since patients often die suddenly due to rupture of large arteries or other hollow organs. [12]
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 [20] Since then, over 600 different mutations have been characterized in the COL3A1 gene. [21] About 2/3 of these mutations change a glycine amino acid to another amino acid in the triple-helical region of the protein chain. [12] A large number of RNA splicing mutations have also been identified. [11] [9] Interestingly, most of these mutations lead to exon skipping, and produce a shorter polypeptide, 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]
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.
 | The 2019 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Helena Kuivaniemi, Gerard Tromp (7 May 2019). "Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases". Gene . Gene Wiki Review Series. 707: 151–171. doi:10.1016/J.GENE.2019.05.003. ISSN 0378-1119. PMC 6579750 . PMID 31075413. Wikidata Q65950306. |
Collagen is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. It is mostly found in connective tissue such as cartilage, bones, tendons, ligaments, and skin. Collagen makes up 30% of the protein found in the human body. Vitamin C is vital for collagen synthesis. Vitamin E improves the production of collagen.
Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders in the current classification, with the latest type discovered in 2018. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.
Collagen, type II, alpha 1 , also known as COL2A1, is a human gene that provides instructions for the production of the pro-alpha1(II) chain of type II collagen.
A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAM-TS2) also known as procollagen I N-proteinase is an enzyme that in humans is encoded by the ADAMTS2 gene.
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.
Collagen alpha-2(XI) chain is a protein that in humans is encoded by the COL11A2 gene.
Lysyl hydroxylases are alpha-ketoglutarate-dependent hydroxylases enzymes that catalyze the hydroxylation of lysine to hydroxylysine. Lysyl hydroxylases require iron and vitamin C as cofactors for their oxidation activity. It takes place following collagen synthesis in the cisternae (lumen) of the rough endoplasmic reticulum (ER). There are three lysyl hydroxylases (LH1-3) encoded in the human genome, namely: PLOD1, PLOD2 and PLOD3. From PLOD2 two splice variant can be expressed, where LH2b differs from LH2a by incorporating the small exon 13A. LH1 and LH3 hydroxylate lysyl residues in the collagen triple helix, whereas LH2b hydroxylates lysyl residues in the telopeptides of collagen. In addition to its hydroxylation activity, LH3 has glycosylation activity that produces either monosaccharide (Gal) or disaccharide (Glc-Gal) attached to collagen hydroxylysines.
Sack–Barabas syndrome is an older name for the medical condition vascular Ehlers–Danlos syndrome (vEDS). It affects the body's blood vessels and organs, making them prone to rupture.
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.
Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinophilic fibers known as collagen fibers, which make up most of the rope-like dense connective tissue in the body. Collagen I itself is created by the combination of both a proalpha1 and a proalpha2 chain created by the COL1alpha1 and COL1alpha2 genes respectively. The Col I gene itself takes up a triple-helical conformation due to its Glycine-X-Y structure, x and y being any type of amino acid. Collagen can also be found in two different isoforms, either as a homotrimer or a heterotrimer, both of which can be found during different periods of development. Heterotrimers, in particular, play an important role in wound healing, and are the dominant isoform found in the body.
A member of the tenascin family, tenascin X (TN-X) also known as flexillin or hexabrachion-like protein is a 450kDa glycoprotein that is expressed in connective tissues. TN-X possesses a modular structure composed, from the N- to the C-terminal part by a Tenascin assembly domain (TAD), a series of 18.5 repeats of epidermal growth factor (EGF)-like motif, a high number of Fibronectin type III (FNIII) module, and a fibrinogen (FBG)-like globular domain. In humans, tenascin X is encoded by the TNXB gene.
Type V collagen is a form of fibrillar collagen associated with classical Ehlers-Danlos syndrome. It is found within the dermal/epidermal junction, placental tissues, as well as in association with tissues containing type I collagen.
Collagen alpha-1(V) chain is a protein that in humans is encoded by the COL5A1 gene.
Collagen alpha-2(V) chain is a protein that in humans is encoded by the COL5A2 gene.
Collagen alpha-2(I) chain is a protein that in humans is encoded by the COL1A2 gene.
Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. It is ubiquitously expressed in many tissues and cell types. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The COL4A1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.
Carbohydrate sulfotransferase 14 is an enzyme that in humans is encoded by the CHST14 gene.
FKBP14 is a gene which codes for a structural protein named FKBP prolyl isomerase 14. This protein is believed to aid in the process of procollagen folding and is located in the endoplasmic reticulum that functions to process and transport proteins. Procollagens are collagen precursors located in the extracellular matrix that give tissues elasticity, strength, and support. This gene is involved in patterning the collagen structure. FKBP prolyl isomerase 14 may also be involved in altering other factors in the extracellular matrix. Mutations of this gene are associated with the kyphoscoliotic type of Ehlers-Danlos syndrome. This condition is characterized by a high range of joint movement, muscle atrophy, curved spine, and delicate cardiovascular vessels. These symptoms are brought about by a loss of the protein which results in a disruption of endoplasmic reticulum activities and extracellular matrix organization. FKBP14 mRNA levels are found higher in ovarian cancer tissues than healthy ovarian tissue and knocked down expression of FKBP14 by lentiviral shRNA leads to an impaired proliferative ability of ovarian cancer cells.
Daniel S. Greenspan is an American biomedical scientist, academic and researcher. He is Kellett professor of Cell and Regenerative Biology at the University of Wisconsin-Madison School of Medicine and Public Health. He has authored over 120 publications. His research has mainly focused on genes encoding proteins of the extracellular space and possible links between defects in such genes and human development and disease.
{{cite book}}: |work= ignored (help)