InterPro : IPR001300

Name  Peptidase C2, calpain, catalytic domain Short Name  Peptidase_C2_calpain_cat
Type  Domain Description  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 []. The protein is a complex of 2polypeptide chains (light and heavy), with three known forms in mammals[, ]: 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 []. 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 [, ]. The crystallographic structure of m-calpain reveals six "domains" in the 80kDa subunit: A 19-amino acid NH2-terminal sequence;Active site domain IIa;Active site domain IIb. Domain 2 showslow levels of sequence similarity to papain; although the catalytic His hasnot been located by biochemical means, it is likely that calpain and papainare related [].Domain III;An 18-amino acid extended sequence linking domain III to domain IV;Domain IV, which resembles the penta EF-hand family of polypeptides, binds calcium and regulates activity []. />]. Ca2+-binding causes a rearrangement of the protein backbone, the net effect of which is that a Trp side chain, which acts as a wedge between catalytic domains IIa and IIb in the apo state, moves away from the active site cleft allowing for the proper formation of the catalytic triad []. 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 knownabout 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 (). 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 []. Calpains are a family of cytosolic cysteine proteinases (see ). Members of the calpain family are believed to function in various biological processes, including integrin-mediated cell migration, cytoskeletal remodeling, cell differentiation and apoptosis [, ].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 [].The crystal structure of calpain has been solved [, ]. 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 [][].The profile covers the whole catalytic domain.
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Sequence Features

GO Displayer

Proteins

InterPro protein domain ID --> Contigs

 

Other

0 Child Features

1 Contains

Id Name Short Name Type
IPR000169 Cysteine peptidase, cysteine active site Pept_cys_AS Active_site

1 Found In

Id Name Short Name Type
IPR022684 Peptidase C2, calpain family Calpain_cysteine_protease Family

0 Parent Features

9 Publications

First Author Title Year Journal Volume Pages
Rawlings ND Families of cysteine peptidases. 1994 Methods Enzymol 244 461-86
Goll DE The calpain system. 2003 Physiol Rev 83 731-801
Sorimachi H Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types. Specific expression of the mRNA in skeletal muscle. 1989 J Biol Chem 264 20106-11
Hata A Tandemly reiterated negative enhancer-like elements regulate transcription of a human gene for the large subunit of calcium-dependent protease. 1989 J Biol Chem 264 6404-11
Khorchid A How calpain is activated by calcium. 2002 Nat Struct Biol 9 239-41
Glading A Cutting to the chase: calpain proteases in cell motility. 2002 Trends Cell Biol 12 46-54
Perrin BJ Calpain. 2002 Int J Biochem Cell Biol 34 722-5
Hosfield CM Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation. 1999 EMBO J 18 6880-9
Moldoveanu T A Ca(2+) switch aligns the active site of calpain. 2002 Cell 108 649-60



To cite PlanMine, please refer to the following publication:

Rozanski, A., Moon, H., Brandl, H., Martín-Durán, J. M., Grohme, M., Hüttner, K., Bartscherer, K., Henry, I., & Rink, J. C.
PlanMine 3.0—improvements to a mineable resource of flatworm biology and biodiversity
Nucleic Acids Research, gky1070. doi:10.1093/nar/gky1070 (2018)