Calpain-2

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
Calpain-2
Identifiers
EC number3.4.22.53
CAS number702693-80-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

This enzyme belongs to the peptidase family C2. It is one of 15 proteins in the calpain family.[3]

Structure

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

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 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

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

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

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. "Structure and nomenclature / Calpain Research Portal: Calpain Structure and Nomenclature". calpain.net. Retrieved 2021-01-17.
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