CysPcCalpain-like thiol protease family.
|SMART accession number:||SM00230|
|Description:||Calpain-like thiol protease family (peptidase family C2). Calcium activated neutral protease (large subunit).|
|Interpro abstract (IPR001300):|
In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:
In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.
Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [(PUBMED:11517925)].
This group of cysteine peptidases belong to the MEROPS peptidase family C2 (calpain family, clan CA). A type example is calpain, which is an intracellular protease involved in many important cellular functions that are regulated by calcium [(PUBMED:2539381)]. The protein is a complex of 2 polypeptide chains (light and heavy), with three known forms in mammals [(PUBMED:7845226), (PUBMED:2555341)]: a highly calcium-sensitive (i.e., micro-molar range) form known as mu-calpain, mu-CANP or calpain I; a form sensitive to calcium in the milli-molar range, known as m-calpain, m-CANP or calpain II; and a third form, known as p94, which is found in skeletal muscle only [(PUBMED:2555341)].
All forms have identical light but different heavy chains. Both mu- and m-calpain are heterodimers containing an identical 28kDa subunit and an 80kDa subunit that shares 55-65% sequence homology between the two proteases [(PUBMED:7845226), (PUBMED:2539381)]. The crystallographic structure of m-calpain reveals six "domains" in the 80kDa subunit:
Calpain-like mRNAs have been identified in other organisms including bacteria, but the molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in these organisms cells is still unclear In metazoans, the activity of calpain is controlled by a single proteinase inhibitor, calpastatin (IPR001259). The calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. The calpains ostensibly participate in a variety of cellular processes including remodelling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma [(PUBMED:12843408)].
Calpains are a family of cytosolic cysteine proteinases. Members of the calpain family are believed to function in various biological processes, including integrin-mediated cell migration, cytoskeletal remodeling, cell differentiation and apoptosis [(PUBMED:11854009), (PUBMED:11950589)].
The calpain family includes numerous members from C. elegans to mammals and with homologues in yeast and bacteria. The best characterised members are the m- and mu-calpains, both proteins are heterodimer composed of a large catalytic subunit and a small regulatory subunit. The large subunit comprises four domains (dI-dIV) while the small subunit has two domains (dV-dVI). Domain dI is a short region cleaved by autolysis, dII is the catalytic core, dIII is a C2-like domain, dIV consists of five calcium binding EF-hand motifs [(PUBMED:11950589)].
The crystal structure of calpain has been solved [(PUBMED:10601010), (PUBMED:11893336)]. The catalytic region consists of two distinct structural domains (dIIa and dIIb). dIIa contains a central helix flanked on three faces by a cluster of alpha-helices and is entirely unrelated to the corresponding domain in the typical thiol proteinases. The fold of dIIb is similar to the corresponding domain in other cysteine proteinases and contains two three-stranded anti-parallel beta-sheets. The catalytic triad residues (C,H,N) are located in dIIa and dIIb. The activation of the domain is dependent on the binding of two calcium atoms in two non EF-hand calcium binding sites located in the catalytic core, one close to the Cys active site in dIIa and one at the end of dIIb. Calcium-binding induced conformational changes in the catalytic domain which align the active site [(PUBMED:11893336)][(PUBMED:11914728)].
The profile covers the whole catalytic domain.
|GO process:||proteolysis (GO:0006508)|
|GO component:||intracellular (GO:0005622)|
|GO function:||calcium-dependent cysteine-type endopeptidase activity (GO:0004198)|
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- Evolution (species in which this domain is found)
- Disease (disease genes where sequence variants are found in this domain)
- Metabolism (metabolic pathways involving proteins which contain this domain)
- Structure (3D structures containing this domain)
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