Calpain-2
From Wikipedia the free encyclopedia
| Calpain-2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.4.22.53 | ||||||||
| CAS no. | 702693-80-9 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
Calpain-2 (EC 3.4.22.53, calcium-activated neutral protease II, m-calpain, milli-calpain) is an intracellular heterodimeric calcium-activated cysteine protease.[1][2] This enzyme catalyses the following chemical reaction
- Broad endopeptidase specificity
This enzyme belongs to the peptidase family C2. It is one of 15 proteins in the calpain family.[3]
Structure[edit]
Calpain-2 is a heterodimer of a catalytic subunit encoded by CAPN2 gene and a regulatory subunit CAPNS1.[1][4][5] The catalytic subunit consists of four domains: protease core 1 domain (PC1), protease core 2 domain (PC2), calpain-type beta-sandwich-like domain (CBSW), and penta EF-hand domain (PEF(L)).[3] The catalytic cleft is formed by PC1 and PC2 upon calcium binding.[6] The catalytic triad consists of residues C105, H262, and N286. Noteworthy, CAPN2 also contains an N-terminal anchor helix, which however is cleaved off upon protease activation.[7] It is believed to play a role in a regulation of catalytic activity.
The regulatory subunit consists of two domains: a glycine-rich domain (GR), and penta EF-hand domain (PEF(S)).[3] The interaction of PEF(S) and PEF(L) through an unpaired EF-hand motif causes dimerization of the two subunits. Calpain-2 heterodimer is highly homologous to calpain-1, which is formed by a catalytic CAPN1 and a regulatory CAPNS1 subunits.[3]
Properties[edit]
There is no known consensus sequence for calpain-2 proteolysis, but there is evidence for over 130 potential substrates.[8] Proteolytic cleavage by calpain-2 is regulated by presence of Ca2+ ions. It requires supraphysiological (low millimolar) concentration of Ca2+ for activation.[6] Intracellular concentration of Ca2+ (approx. 100 nM)[9] is insufficient for activating calpain-2, so activation occurs upon influx of ions from extracellular space or from endoplasmic reticulum. In addition, calpain-1/2 can be inhibited by calpastatin (encoded by the CAST gene) which binds to the PEF domains of the catalytic and regulatory subunits of calpains-1/2. It prohibits substrate binding to the active site through steric hindrance.[10]
Calpain-2 in Cancer[edit]
Upregulation of calpain-2 is linked to increased aggressiveness of cancer.[11][12] There is evidence suggesting that the mechanism of action is through cleavage of substrates involved in cell migration, invasion, and sensitivity to chemotherapeutic agents.[13][14][15]
Domain Nomenclature[edit]
Previously used nomenclature used Roman numerals to denote calpain-2 domains starting from the N-terminus of CAPN2 and ending at C-terminus of CAPNS1. For example, PEF(L) and PEF(S) were referred to as Domain IV and Domain VI, respectively.[16]
See also[edit]
References[edit]
- ^ a b Strobl S, Fernandez-Catalan C, Braun M, Huber R, Masumoto H, Nakagawa K, et al. (January 2000). "The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium". Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 588–92. Bibcode:2000PNAS...97..588S. doi:10.1073/pnas.97.2.588. PMC 15374. PMID 10639123.
- ^ Dutt P, Spriggs CN, Davies PL, Jia Z, Elce JS (October 2002). "Origins of the difference in Ca2+ requirement for activation of mu- and m-calpain". The Biochemical Journal. 367 (Pt 1): 263–9. doi:10.1042/bj20020485. PMC 1222847. PMID 12014988.
- ^ a b c d Ono Y, Sorimachi H (January 2012). "Calpains: an elaborate proteolytic system". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1824 (1): 224–36. doi:10.1016/j.bbapap.2011.08.005. PMID 21864727.
- ^ Hosfield CM, Elce JS, Davies PL, Jia Z (December 1999). "Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation". The EMBO Journal. 18 (24): 6880–9. doi:10.1093/emboj/18.24.6880. PMC 1171751. PMID 10601010.
- ^ Dutt P, Arthur JS, Croall DE, Elce JS (October 1998). "m-Calpain subunits remain associated in the presence of calcium". FEBS Letters. 436 (3): 367–71. doi:10.1016/s0014-5793(98)01167-3. PMID 9801150.
- ^ a b Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL (March 2002). "A Ca(2+) switch aligns the active site of calpain". Cell. 108 (5): 649–60. doi:10.1016/S0092-8674(02)00659-1. PMID 11893336. S2CID 15607738.
- ^ Chou JS, Impens F, Gevaert K, Davies PL (July 2011). "m-Calpain activation in vitro does not require autolysis or subunit dissociation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (7): 864–72. doi:10.1016/j.bbapap.2011.04.007. PMID 21549862.
- ^ Liu Z, Cao J, Gao X, Ma Q, Ren J, Xue Y (April 2011). "GPS-CCD: a novel computational program for the prediction of calpain cleavage sites". PLOS ONE. 6 (4): e19001. Bibcode:2011PLoSO...619001L. doi:10.1371/journal.pone.0019001. PMC 3080405. PMID 21533053.
- ^ Breitwieser GE (2008). "Extracellular calcium as an integrator of tissue function". The International Journal of Biochemistry & Cell Biology. 40 (8): 1467–80. doi:10.1016/j.biocel.2008.01.019. PMC 2441573. PMID 18328773.
- ^ Hanna RA, Campbell RL, Davies PL (November 2008). "Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin". Nature. 456 (7220): 409–12. Bibcode:2008Natur.456..409H. doi:10.1038/nature07451. PMID 19020623. S2CID 4399656.
- ^ Storr SJ, Carragher NO, Frame MC, Parr T, Martin SG (May 2011). "The calpain system and cancer". Nature Reviews. Cancer. 11 (5): 364–74. doi:10.1038/nrc3050. PMID 21508973. S2CID 23555255.
- ^ Storr SJ, Safuan S, Woolston CM, Abdel-Fatah T, Deen S, Chan SY, Martin SG (October 2012). "Calpain-2 expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer". Journal of Cellular and Molecular Medicine. 16 (10): 2422–8. doi:10.1111/j.1582-4934.2012.01559.x. PMC 3472029. PMID 22435971.
- ^ Franco SJ, Huttenlocher A (September 2005). "Regulating cell migration: calpains make the cut". Journal of Cell Science. 118 (Pt 17): 3829–38. doi:10.1242/jcs.02562. PMID 16129881.
- ^ Grieve S, Gao Y, Hall C, Hu J, Greer PA (August 2016). "Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis". Molecular and Cellular Biology. 36 (15): 2078–88. doi:10.1128/MCB.01062-15. PMC 4946432. PMID 27215381.
- ^ MacLeod JA, Gao Y, Hall C, Muller WJ, Gujral TS, Greer PA (September 2018). "Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib". Oncotarget. 9 (70): 33382–33395. doi:10.18632/oncotarget.26078. PMC 6161787. PMID 30279968.
- ^ "Structure and nomenclature / Calpain Research Portal: Calpain Structure and Nomenclature". calpain.net. Retrieved 2021-01-17.
External links[edit]
- Calpain-2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
