type-III collagen
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Type III Collagen is a homotrimer, or a protein composed of three identical
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
chains (
monomers In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
), 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
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. Type III collagen is one of the fibrillar collagens whose proteins have a long, inflexible, triple-helical domain.


Protein structure and function

Type III collagen is synthesized by cells as a pre-procollagen. The signal peptide is cleaved off producing a procollagen molecule. Three identical type III procollagen chains come together at the
carboxy-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
ends, and the structure is stabilized by the formation of
disulphide bonds In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. 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 Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
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 Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
, and some lysine as well as hydroxylysine residues undergo oxidative deamination catalysed by
lysyl oxidase Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is an enzyme that, in humans, is encoded by the ''LOX'' gene. It catalyzes the conversion of lysine molecules into highly reactive aldehydes that form cross-links in extracellular matr ...
. 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 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 who ...
. 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 gene is located on the long (q) arm of chromosome 2 at 2q32.2, between positions and . The gene has 51 exons and is approximately 40  kbp long. The ''COL3A1'' gene is in tail-to-tail orientation with a gene for another fibrillar collagen, namely . Two transcripts are generated from the gene using different polyadenylation sites. 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. 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.


Clinical significance

Mutations in the 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. A few patients with arterial aneurysms without clear signs of EDS have also been found to have ''COL3A1'' mutations. 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. 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 Since then, over 600 different mutations have been characterized in the ''COL3A1'' gene. About 2/3 of these mutations change a glycine amino acid to another amino acid in the triple-helical region of the protein chain. A large number of RNA splicing mutations have also been identified. Interestingly, most of these mutations lead to
exon skipping In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation. Mechanis ...
, 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. 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. Another important clinical implication is that several studies have reported on mosaicism. 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. 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. 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.


Animal models

Four different mouse models with defects have been reported. 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


References


Further reading

* * * * * * * *


External links

* * * * {{Fibrous proteins Collagens