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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 366 216-29 (2007)
Cited: 29 times
EuropePMC logo PMID: 17157313

Abstract

Calpains are calcium activated cysteine proteases found throughout the animal, plant, and fungi kingdoms; 14 isoforms have been described in the human genome. Calpains have been implicated in multiple models of human disease; for instance, calpain 1 is activated in the brains of individuals with Alzheimer's disease, and the digestive tract specific calpain 9 is down-regulated in gastric cancer cell lines. We have solved the structures of human calpain 1 and calpain 9 protease cores using crystallographic methods; both structures have clear implications for the function of non-catalytic domains of full-length calpains in the calcium-mediated activation of the enzyme. The structure of minicalpain 1 is similar to previously solved structures of the protease core. Auto-inhibition in this system is most likely through rearrangements of a central helical/loop region near the active site cysteine, which occlude the substrate binding site. However, the structure of minicalpain 9 indicates that auto-inhibition in this enzyme is mediated through large intra-domain movements that misalign the catalytic triad. This disruption is reminiscent of the full-length inactive calpain conformation. The structures of the highly conserved, ubiquitously expressed human calpain 1 and the more tissue specific human calpain 9 indicate that although there are high levels of sequence conservation throughout the calpain family, isolated structures of family members are insufficient to explain the molecular mechanism of activation for this group of proteins.

Articles - 1ziv mentioned but not cited (5)

  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. A novel de novo CAPN5 mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay. Velez G, Bassuk AG, Schaefer KA, Brooks B, Gakhar L, Mahajan M, Kahn P, Tsang SH, Ferguson PJ, Mahajan VB. Cold Spring Harb Mol Case Stud 4 a002519 (2018)
  3. Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains. Gakhar L, Bassuk AG, Velez G, Khan S, Yang J, Tsang SH, Mahajan VB. J Struct Biol 196 309-318 (2016)
  4. Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants. Velez G, Sun YJ, Khan S, Yang J, Herrmann J, Chemudupati T, MacLaren RE, Gakhar L, Wakatsuki S, Bassuk AG, Mahajan VB. Cell Rep 30 881-892.e5 (2020)
  5. CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials. Wert KJ, Koch SF, Velez G, Hsu CW, Mahajan M, Bassuk AG, Tsang SH, Mahajan VB. Hum Mutat 40 2377-2392 (2019)


Reviews citing this publication (6)

  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. Structural genomics and drug discovery: all in the family. Weigelt J, McBroom-Cerajewski LD, Schapira M, Zhao Y, Arrowsmith CH. Curr Opin Chem Biol 12 32-39 (2008)
  5. Calpain-2 as a therapeutic target for acute neuronal injury. Wang Y, Bi X, Baudry M. Expert Opin Ther Targets 22 19-29 (2018)
  6. Calpain Regulation and Dysregulation-Its Effects on the Intercalated Disk. Yoder MW, Wright NT, Borzok MA. Int J Mol Sci 24 11726 (2023)

Articles citing this publication (18)

  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. Calpain 8/nCL-2 and calpain 9/nCL-4 constitute an active protease complex, G-calpain, involved in gastric mucosal defense. Hata S, Abe M, Suzuki H, Kitamura F, Toyama-Sorimachi N, Abe K, Sakimura K, Sorimachi H. PLoS Genet 6 e1001040 (2010)
  3. 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)
  4. Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions. Qian J, Cuerrier D, Davies PL, Li Z, Powers JC, Campbell RL. J Med Chem 51 5264-5270 (2008)
  5. Genome-wide association study identifies a possible susceptibility locus for endometrial cancer. Long J, Zheng W, Xiang YB, Lose F, Thompson D, Tomlinson I, Yu H, Wentzensen N, Lambrechts D, Dörk T, Dubrowinskaja N, Goodman MT, Salvesen HB, Fasching PA, Scott RJ, Delahanty R, Zheng Y, O'Mara T, Healey CS, Hodgson S, Risch H, Yang HP, Amant F, Turmanov N, Schwake A, Lurie G, Trovik J, Beckmann MW, Ashton K, Ji BT, Bao PP, Howarth K, Lu L, Lissowska J, Coenegrachts L, Kaidarova D, Dürst M, Thompson PJ, Krakstad C, Ekici AB, Otton G, Shi J, Zhang B, Gorman M, Brinton L, Coosemans A, Matsuno RK, Halle MK, Hein A, Proietto A, Cai H, Lu W, Dunning A, Easton D, Gao YT, Cai Q, Spurdle AB, Shu XO. Cancer Epidemiol Biomarkers Prev 21 980-987 (2012)
  6. Decreased expression of Calpain-9 predicts unfavorable prognosis in patients with gastric cancer. Peng P, Wu W, Zhao J, Song S, Wang X, Jia D, Shao M, Zhang M, Li L, Wang L, Duan F, Zhao R, Yang C, Wu H, Zhang J, Shen Z, Ruan Y, Gu J. Sci Rep 6 29604 (2016)
  7. Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis. Kim DH, Beckett JD, Nagpal V, Seman-Senderos MA, Gould RA, Creamer TJ, MacFarlane EG, Chen Y, Bedja D, Butcher JT, Mitzner W, Rouf R, Hata S, Warren DS, Dietz HC. Sci Transl Med 11 eaau2814 (2019)
  8. Role of calpain-9 and PKC-delta in the apoptotic mechanism of lumen formation in CEACAM1 transfected breast epithelial cells. Chen CJ, Nguyen T, Shively JE. Exp Cell Res 316 638-648 (2010)
  9. 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)
  10. 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)
  11. A Gastrointestinal Calpain Complex, G-calpain, Is a Heterodimer of CAPN8 and CAPN9 Calpain Isoforms, Which Play Catalytic and Regulatory Roles, Respectively. Hata S, Kitamura F, Yamaguchi M, Shitara H, Murakami M, Sorimachi H. J Biol Chem 291 27313-27322 (2016)
  12. Expression of calpain-calpastatin system (CCS) member proteins in human lymphocytes of young and elderly individuals; pilot baseline data for the CALPACENT project. Mikosik A, Foerster J, Jasiulewicz A, Frąckowiak J, Colonna-Romano G, Bulati M, Buffa S, Martorana A, Caruso C, Bryl E, Witkowski JM. Immun Ageing 10 27 (2013)
  13. 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)
  14. The zinc fingers of the small optic lobes calpain bind polyubiquitin. Hastings MH, Qiu A, Zha C, Farah CA, Mahdid Y, Ferguson L, Sossin WS. J Neurochem 146 429-445 (2018)
  15. Homology modeling study of bovine μ-calpain inhibitor-binding domains. Chai HH, Lim D, Lee SH, Chai HY, Jung E. Int J Mol Sci 15 7897-7938 (2014)
  16. 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)
  17. Impaired activity and membrane association of most calpain-5 mutants causal for neovascular inflammatory vitreoretinopathy. Geddes JW, Bondada V, Croall DE, Rodgers DW, Gal J. Biochim Biophys Acta Mol Basis Dis 1869 166747 (2023)
  18. Molecular dynamic simulations of the catalytic subunit of calpains 1, 2, 5, and 10: Structural analysis with an aim toward drug design. Romo-Mancillas A, Lemus R, Pérez-Estrada R, Kuribreña-Romero de Terreros F, Domínguez-Ramírez L. Chem Biol Drug Des 93 38-49 (2019)


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