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Calpain silencing by a reversible intrinsic mechanism.

Moldoveanu T, Hosfield CM, Lim D, Jia Z, Davies PL
Nat Struct Biol 10 371-8 (2003)
Cited: 43 times
EuropePMC logo PMID: 12665854

Abstract

Uncontrolled activation of calpain can lead to necrotic cell death and irreversible tissue damage. We have discovered an intrinsic mechanism whereby the autolysis-generated protease core fragment of calpain is inactivated through the inherent instability of a key alpha-helix. This auto-inactivation state was captured by the 1.9 A Ca(2+)-bound structure of the protease core from m-calpain, and sequence alignments suggest that it applies to about half of the calpain isoforms. Intact calpain large subunits are also subject to this inhibition, which can be prevented through assembly of the heterodimers. Other isoforms or their released cores are not silenced by this mechanism and might contribute to calpain patho-physiologies.

Articles - 1mdw mentioned but not cited (7)

  1. Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment. Bassuk AG, Yeh S, Wu S, Martin DF, Tsang SH, Gakhar L, Mahajan VB. PLoS One 10 e0122352 (2015)
  2. Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation. Ye Q, Campbell RL, Davies PL. J Biol Chem 293 4056-4070 (2018)
  3. The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation. Ono Y, Shindo M, Doi N, Kitamura F, Gregorio CC, Sorimachi H. Proc Natl Acad Sci U S A 111 E5527-36 (2014)
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  5. Identification of active Plasmodium falciparum calpain to establish screening system for Pf-calpain-based drug development. Soh BY, Song HO, Lee Y, Lee J, Kaewintajuk K, Lee B, Choi YY, Cho JH, Choi S, Park H. Malar J 12 47 (2013)
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  7. A mouse model of miR-96, miR-182 and miR-183 misexpression implicates miRNAs in cochlear cell fate and homeostasis. Weston MD, Tarang S, Pierce ML, Pyakurel U, Rocha-Sanchez SM, McGee J, Walsh EJ, Soukup GA. Sci Rep 8 3569 (2018)


Reviews citing this publication (9)

  1. Calpain research for drug discovery: challenges and potential. Ono Y, Saido TC, Sorimachi H. Nat Rev Drug Discov 15 854-876 (2016)
  2. Structure-function relationships in calpains. Campbell RL, Davies PL. Biochem J 447 335-351 (2012)
  3. Calpain chronicle--an enzyme family under multidisciplinary characterization. Sorimachi H, Hata S, Ono Y. Proc Jpn Acad Ser B Phys Biol Sci 87 287-327 (2011)
  4. Regulation and physiological roles of the calpain system in muscular disorders. Sorimachi H, Ono Y. Cardiovasc Res 96 11-22 (2012)
  5. Impact of genetic insights into calpain biology. Sorimachi H, Hata S, Ono Y. J Biochem 150 23-37 (2011)
  6. Expanding members and roles of the calpain superfamily and their genetically modified animals. Sorimachi H, Hata S, Ono Y. Exp Anim 59 549-566 (2010)
  7. Epidemiology and economic burden of measles, mumps, pertussis, and varicella in Germany: a systematic review. Damm O, Witte J, Wetzka S, Prosser C, Braun S, Welte R, Greiner W. Int J Public Health 61 847-860 (2016)
  8. The calpain system and diabetes. Pandurangan M, Hwang I, Orhirbat C, Jieun Y, Cho SH. Pathophysiology 21 161-167 (2014)
  9. Emerging roles of calpain proteolytic systems in macrophage cholesterol handling. Miyazaki T, Miyazaki A. Cell Mol Life Sci 74 3011-3021 (2017)

Articles citing this publication (27)

  1. Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains. Moldoveanu T, Gehring K, Green DR. Nature 456 404-408 (2008)
  2. Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization. Fernández-Montalván A, Bouwmeester T, Joberty G, Mader R, Mahnke M, Pierrat B, Schlaeppi JM, Worpenberg S, Gerhartz B. FEBS J 274 4256-4270 (2007)
  3. Crystal structures of calpain-E64 and -leupeptin inhibitor complexes reveal mobile loops gating the active site. Moldoveanu T, Campbell RL, Cuerrier D, Davies PL. J Mol Biol 343 1313-1326 (2004)
  4. Association of calpastatin with inactive calpain: a novel mechanism to control the activation of the protease? Melloni E, Averna M, Stifanese R, De Tullio R, Defranchi E, Salamino F, Pontremoli S. J Biol Chem 281 24945-24954 (2006)
  5. Calpain activation by cooperative Ca2+ binding at two non-EF-hand sites. Moldoveanu T, Jia Z, Davies PL. J Biol Chem 279 6106-6114 (2004)
  6. The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition. Davis TL, Walker JR, Finerty PJ, Mackenzie F, Newman EM, Dhe-Paganon S. J Mol Biol 366 216-229 (2007)
  7. CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model. Wert KJ, Bassuk AG, Wu WH, Gakhar L, Coglan D, Mahajan M, Wu S, Yang J, Lin CS, Tsang SH, Mahajan VB. Hum Mol Genet 24 4584-4598 (2015)
  8. Development of calpain-specific inactivators by screening of positional scanning epoxide libraries. Cuerrier D, Moldoveanu T, Campbell RL, Kelly J, Yoruk B, Verhelst SHL, Greenbaum D, Bogyo M, Davies PL. J Biol Chem 282 9600-9611 (2007)
  9. Crystal structure of a micro-like calpain reveals a partially activated conformation with low Ca2+ requirement. Pal GP, De Veyra T, Elce JS, Jia Z. Structure 11 1521-1526 (2003)
  10. Cys-His proteases are among the wired proteins of the cell. Lockwood TD. Arch Biochem Biophys 432 12-24 (2004)
  11. Calpain-7 binds to CHMP1B at its second α-helical region and forms a ternary complex with IST1. Maemoto Y, Osako Y, Goto E, Nozawa E, Shibata H, Maki M. J Biochem 150 411-421 (2011)
  12. Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10. Yan Q, Huang C, Jiang Y, Shan H, Jiang R, Wang J, Liu J, Ding L, Yan G, Sun H. Cell Death Dis 9 291 (2018)
  13. Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19(INK4d). Joy J, Nalabothula N, Ghosh M, Popp O, Jochum M, Machleidt W, Gil-Parrado S, Holak TA. Biol Chem 387 329-335 (2006)
  14. Studies on aromatic compounds: inhibition of calpain I by biphenyl derivatives and peptide-biphenyl hybrids. Montero A, Alonso M, Benito E, Benito E, Chana A, Mann E, Navas JM, Herradón B. Bioorg Med Chem Lett 14 2753-2757 (2004)
  15. Calpain-2 participates in the process of calpain-1 inactivation. Shinkai-Ouchi F, Shindo M, Doi N, Hata S, Ono Y. Biosci Rep 40 BSR20200552 (2020)
  16. Interaction between catalytically inactive calpain and calpastatin. Evidence for its occurrence in stimulated cells. Averna M, Stifanese R, De Tullio R, Defranchi E, Salamino F, Melloni E, Pontremoli S. FEBS J 273 1660-1668 (2006)
  17. Ritonavir does not inhibit calpain in vitro. Cuerrier D, Nie Z, Badley AD, Davies PL. Biochem Biophys Res Commun 327 208-211 (2005)
  18. Solution structure of the Apo C-terminal domain of the Lethocerus F1 troponin C isoform. De Nicola GF, Martin S, Bullard B, Pastore A. Biochemistry 49 1719-1726 (2010)
  19. The importance of conserved amino acid residues in p94 protease sub-domain IIb and the IS2 region for constitutive autolysis. Ono Y, Hayashi C, Doi N, Tagami M, Sorimachi H. FEBS Lett 582 691-698 (2008)
  20. Electrostatic interactions of domain III stabilize the inactive conformation of mu-calpain. Fernández-Montalván A, Assfalg-Machleidt I, Pfeiler D, Fritz H, Jochum M, Machleidt W. Biochem J 382 607-617 (2004)
  21. Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors. Jones MA, Morton JD, Coxon JM, McNabb SB, Lee HY, Aitken SG, Mehrtens JM, Robertson LJ, Neffe AT, Miyamoto S, Bickerstaffe R, Gately K, Wood JM, Abell AD. Bioorg Med Chem 16 6911-6923 (2008)
  22. The C2 domain of calpain 5 contributes to enzyme activation and membrane localization. Bondada V, Gal J, Mashburn C, Rodgers DW, Larochelle KE, Croall DE, Geddes JW. Biochim Biophys Acta Mol Cell Res 1868 119019 (2021)
  23. Calpainopathy: Description of a Novel Mutation and Clinical Presentation with Early Severe Contractures. Landires I, Núñez-Samudio V, Fernandez J, Sarria C, Villareal V, Córdoba F, Apráez-Ippolito G, Martínez S, Vidal OM, Vélez JI, Arcos-Holzinger M, Landires S, Arcos-Burgos M. Genes (Basel) 11 E129 (2020)
  24. Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes. Vaughan RH, Kresse JC, Farmer LK, Thézénas ML, Kessler BM, Lindeman JHN, Sharples EJ, Welsh GI, Nørregaard R, Ploeg RJ, Kaisar M. Am J Transplant 22 1073-1087 (2022)
  25. Expression of human, mouse, and rat m-calpains in Escherichia coli and in murine fibroblasts. Larsen AK, De Veyra T, Jia Z, Wells A, Dutt P, Elce JS. Protein Expr Purif 33 246-255 (2004)
  26. Visualizing Cell Death in Live Retina: Using Calpain Activity Detection as a Biomarker for Retinal Degeneration. Belhadj S, Hermann NS, Zhu Y, Christensen G, Strasser T, Paquet-Durand F. Int J Mol Sci 23 3892 (2022)
  27. Computational investigation of the key factors affecting the second stage activation mechanisms of domain II m-calpain. Bhatti G, Jayanthi L, VandeVord P, Gebremichael Y. J Mol Model 19 779-792 (2013)


Related citations provided by authors (2)

  1. A Ca(2+) Switch Aligns the Active Site of Calpain. Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL Cell 108 649-660 (2002)
  2. Crystal Structure of Calpain Reveals the Structural Basis for Ca(2+)-dependent Protease Activity and a Novel Mode of Enzyme Activation. Hosfield CM, Elce JS, Davies PL, Jia Z EMBO J. 18 6880-6889 (1999)

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