CAPN:4xCa2+:CAPNS cleave cytoskeletal proteins

Stable Identifier
Reaction [transition]
Homo sapiens
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Calpains (EC; CAPN, Clan CA, family C02) constitute a distinct group of intracellular cysteine proteases found in almost all eukaryotes and a few bacteria. Calpains can be described as cytosolic proteases exhibiting Ca2+-dependent limited proteolytic activity which function to transform or modulate their substrate proteins' structures and activities; they are therefore called modulator proteases. As calpains selectively cleave proteins in response to calcium signals, they have the potential to influence cellular functions such as signal transduction, cytoskeletal remodelling, cell motility, membrane repair, cell cycle progression, gene expression and apoptosis (Sorimachi et al. 2010). Calpain deficiencies are linked to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy and diabetes (Sorimachi et al. 2011).

The human genome has 15 genes (named using formal nomenclature as CAPN1, CAPN2, etc.) that encode a calpain-like protease domain. The two best-characterised members of the calpain family, CAPN1 and 2, are ubiquitously expressed and locate to the cytosol of the cell (Goll et al. 2003). All other calpains annotated here are assumed to be functionally similar to these two based on their structural similarites. They are heterodimers, consisting of a common small regulatory subunit (CAPNS1 or CAPNS2; ca. 30kDa) and a large, isoform-specific catalytic subunit. Three-dimensional structural analyses reveal the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to ca. four Ca2+ ions via well-conserved amino acids. So, despite the fact that they have divergent domain structures, calpains share this mechanistic functional character (Croall & Ersfeld 2007, Sorimachi et al. 2011, Ono & Sorimachi 2012).

Calpain activity is tightly regulated by the endogenous inhibitor calpastatin (CAST), which is capable of reversibly binding and inhibiting four molecules of calpain in the presence of calcium. This suggests calpains are transiently activated by high Ca2+ concentrations such as a Ca2+ influx, and then return to an inactive state ready for reactivation (Campbell & Davies 2012).
Literature References
PubMed ID Title Journal Year
21670566 Calpain chronicle--an enzyme family under multidisciplinary characterization

Hata, S, Ono, Y, Sorimachi, H

Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2011
21864727 Calpains: an elaborate proteolytic system

Ono, Y, Sorimachi, H

Biochim. Biophys. Acta 2012
12843408 The calpain system

Cong, J, Goll, DE, Thompson, VF, Li, H, Wei, W

Physiol. Rev. 2003
21030783 Expanding members and roles of the calpain superfamily and their genetically modified animals

Hata, S, Ono, Y, Sorimachi, H

Exp. Anim. 2010
23035980 Structure-function relationships in calpains

Campbell, RL, Davies, PL

Biochem. J. 2012
17608959 The calpains: modular designs and functional diversity

Croall, DE, Ersfeld, K

Genome Biol. 2007
Catalyst Activity

calcium-dependent cysteine-type endopeptidase activity of CAPN:4xCa2+:CAPNS [cytosol]

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