Definition: Calpains are a large family of intracellular proteases whose precise and limited cleavage of specific proteins might be an integral regulatory aspect of signaling pathways. They are nonlysosomal intracellular cysteine proteases that requires calcium for its catalytic activity.

The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits.

Members

The mammalian calpains include 2 ubiquitous proteins, CAPN1 (MIM.114220) and CAPN2 (MIM.114230), as well as 2 stomach-specific proteins, and CAPN3, which is muscle-specific.

The ubiquitous enzymes consist of heterodimers with distinct large subunits associated with a common small subunit, all of which are encoded by different genes. They are heterodimers composed of L (large, catalytic, 80 kD) and S (small, regulatory, 30 kD) subunits. The isozymes share an identical S subunit (114170); differences arise from the L subunits (L1 and L2).

The large subunits of calpains can be subdivided into 4 domains; domains I and III, whose functions remain unknown, show no homology with known proteins. The former, however, may be important for the regulation of the proteolytic activity. Domain II shows similarity with other cysteine proteases, which share histidine, cysteine, and asparagine residues at their active sites. Domain IV comprises 4 EF-hand structures that are potential calcium-binding sites. In addition, 3 unique regions with no known homology are present in the muscle-specific CAPN protein, namely NS, IS1, and IS2, the latter containing a nuclear translocation signal.

Function

 cellular motility

• integrin-mediated cellular migration

Pathology

 calpain-10 (CAPN10): variation in type 2 diabetes susceptibility.

 calpain-3 (CAPN3) (MIM.114240): mutations in limb-girdle type 2a muscular dystrophy

 oncogenesis: many gene products associated with carcinogenesis are substrates of calpain family enzymes, including FOS (MIM.164810), JUN (MIM.165160), p53 (MIM.191170), and ESR1 (MIM.133430).

Members

 calpain-1 (MIM.114220)
 calpain-2 (MIM.114230)
 calpain-3 (MIM.114240) : mutations in limb-girdle type 2a muscular dystrophy
 calpain-4 (MIM.114170)
 calpain-5 (MIM.602537)
 calpain-6 (MIM.300146)
 calpain-7 (MIM.606400)
 calpain-8
 calpain-9 (MIM.606401)
 calpain-10 (MIM.605286) : Variants in susceptibility to type 2 diabetes or noninsulin-dependent diabetes mellitus (NIDDM) (MIM.125853)
 calpain-11 (MIM.604822)

References

 Zatz M, Starling A. Calpains and disease. N Engl J Med. 2005 Jun 9;352(23):2413-23. PMID: #15944426#

 Biswas S, Harris F, Dennison S, Singh J, Phoenix DA. Calpains: targets of cataract prevention? Trends Mol Med. 2004 Feb;10(2):78-84. PMID: #15102361#

 Glading A, Lauffenburger DA, Wells A. Cutting to the chase: calpain proteases in cell motility. Trends Cell Biol. 2002 Jan;12(1):46-54. PMID: #11854009#

 Huang Y, Wang KK. The calpain family and human disease. Trends Mol Med. 2001 Aug;7(8):355-62. PMID: #11516996#