Calpain-2 - Misplaced Pages

Calpain-2 (EC 3.4.22.53, calcium-activated neutral protease II, m-calpain, milli-calpain) is an intracellular heterodimeric calcium-activated cysteine protease. 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.

Structure

Calpain-2 is a heterodimer of a catalytic subunit encoded by CAPN2 gene and a regulatory subunit CAPNS1. 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. 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. 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. Proteolytic cleavage by calpain-2 is regulated by presence of Ca ions. It requires supraphysiological (low millimolar) concentration of Ca for activation. Intracellular concentration of Ca (approx. 100 nM) 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.

Calpain-2 in Cancer

Upregulation of calpain-2 is linked to increased aggressiveness of cancer. There is evidence suggesting that the mechanism of action is through cleavage of substrates involved in cell migration, invasion, and sensitivity to chemotherapeutic agents.

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.

References

^ 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.
^ 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.
^ 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

Calpain-2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

v t e Proteases: cysteine proteases (EC 3.4.22)
Caspase	Caspase 1 Caspase 2 Caspase 3 Caspase 4 Caspase 5 Caspase 6 Caspase 7 Caspase 8 Caspase 9 Caspase 10 Caspase 12 Caspase 13 Caspase 14
Fruit-derived	Papain Ficain Bromelain Actinidain
Calpain	CAPN1 CAPN2 CAPN3 CAPN5 CAPN6 CAPN7 CAPN8 CAPN9 CAPN10 CAPN11 CAPN12 CAPN13 CAPN14 CAPNS1 CAPNS2
Cathepsin	B C F H K L1/L2 O S W Z
Other	Clostripain Cancer procoagulant Separase Autophagin Cruzipain 3C-like protease Gingipain R Gingipain K

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Portal:

Biology

Category:

EC 3.4.22