Calpain-2 Explained

Calpain-2
Ec Number:3.4.22.53
Cas Number:702693-80-9

Calpain-2 (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

Calpain-2 is a heterodimer of a catalytic subunit encoded by CAPN2 gene and a regulatory subunit CAPNS1.[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)). 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)). 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.

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 supraphysiological (low millimolar) concentration of Ca2+ for activation. 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

Notes and References

  1. Strobl S, Fernandez-Catalan C, Braun M, Huber R, Masumoto H, Nakagawa K, Irie A, Sorimachi H, Bourenkow G, Bartunik H, Suzuki K, Bode W . 6 . 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 . January 2000 . 10639123 . 15374 . 10.1073/pnas.97.2.588 . 2000PNAS...97..588S . free .
  2. Dutt P, Spriggs CN, Davies PL, Jia Z, Elce JS . Origins of the difference in Ca2+ requirement for activation of mu- and m-calpain . The Biochemical Journal . 367 . Pt 1 . 263–9 . October 2002 . 12014988 . 1222847 . 10.1042/bj20020485 .
  3. Ono Y, Sorimachi H . Calpains: an elaborate proteolytic system . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1824 . 1 . 224–36 . January 2012 . 21864727 . 10.1016/j.bbapap.2011.08.005 . free .
  4. Hosfield CM, Elce JS, Davies PL, Jia Z . 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 . December 1999 . 10601010 . 1171751 . 10.1093/emboj/18.24.6880 .
  5. Dutt P, Arthur JS, Croall DE, Elce JS . m-Calpain subunits remain associated in the presence of calcium . FEBS Letters . 436 . 3 . 367–71 . October 1998 . 9801150 . 10.1016/s0014-5793(98)01167-3 .
  6. Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL . A Ca(2+) switch aligns the active site of calpain . English . Cell . 108 . 5 . 649–60 . March 2002 . 11893336 . 10.1016/S0092-8674(02)00659-1 . 15607738 . free .
  7. Chou JS, Impens F, Gevaert K, Davies PL . m-Calpain activation in vitro does not require autolysis or subunit dissociation . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1814 . 7 . 864–72 . July 2011 . 21549862 . 10.1016/j.bbapap.2011.04.007 .
  8. Liu Z, Cao J, Gao X, Ma Q, Ren J, Xue Y . GPS-CCD: a novel computational program for the prediction of calpain cleavage sites . PLOS ONE . 6 . 4 . e19001 . April 2011 . 21533053 . 3080405 . 10.1371/journal.pone.0019001 . 2011PLoSO...619001L . free .
  9. Breitwieser GE . Extracellular calcium as an integrator of tissue function . The International Journal of Biochemistry & Cell Biology . 40 . 8 . 1467–80 . 2008 . 18328773 . 2441573 . 10.1016/j.biocel.2008.01.019 .
  10. Hanna RA, Campbell RL, Davies PL . Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin . Nature . 456 . 7220 . 409–12 . November 2008 . 19020623 . 10.1038/nature07451 . 2008Natur.456..409H . 4399656 .
  11. Storr SJ, Carragher NO, Frame MC, Parr T, Martin SG . The calpain system and cancer . Nature Reviews. Cancer . 11 . 5 . 364–74 . May 2011 . 21508973 . 10.1038/nrc3050 . 23555255 .
  12. Storr SJ, Safuan S, Woolston CM, Abdel-Fatah T, Deen S, Chan SY, Martin SG . 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 . October 2012 . 22435971 . 3472029 . 10.1111/j.1582-4934.2012.01559.x .
  13. Franco SJ, Huttenlocher A . Regulating cell migration: calpains make the cut . Journal of Cell Science . 118 . Pt 17 . 3829–38 . September 2005 . 16129881 . 10.1242/jcs.02562 . free .
  14. Grieve S, Gao Y, Hall C, Hu J, Greer PA . Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis . Molecular and Cellular Biology . 36 . 15 . 2078–88 . August 2016 . 27215381 . 4946432 . 10.1128/MCB.01062-15 .
  15. MacLeod JA, Gao Y, Hall C, Muller WJ, Gujral TS, Greer PA . 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 . September 2018 . 30279968 . 6161787 . 10.18632/oncotarget.26078 .
  16. Web site: Structure and nomenclature / Calpain Research Portal: Calpain Structure and Nomenclature. 2021-01-17. calpain.net.

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