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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 1521-6 (2003)
Cited: 22 times
EuropePMC logo PMID: 14656436

Abstract

The two Ca2+-dependent cysteine proteases, micro- and m-calpain, are involved in various Ca2+-linked signal pathways but differ markedly in their Ca2+ requirements for activation. We have determined the structure of a micro-like calpain, which has 85% micro-calpain sequence (the first 48 and the last 62 residues of the large subunit are those from m-calpain) and a low Ca2+ requirement. This construct was used because micro-calpain itself is too poorly expressed. The structure of micro-like calpain is very similar in overall fold to that of m-calpain as expected, but differs significantly in two aspects. In comparison with m-calpain, the catalytic triad residues in micro-like calpain, His and Cys, are much closer together in the absence of Ca2+, and significant portions of the Ca2+ binding EF-hand motifs are disordered and more flexible. These structural differences imply that Ca2+-free micro-calpain may represent a partially activated structure, requiring lower Ca2+ concentration to trigger its activation.

Articles - 1qxp mentioned but not cited (7)

  1. 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)
  2. 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)
  3. 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)
  4. A Compound Heterozygous Mutation in Calpain 1 Identifies a New Genetic Cause for Spinal Muscular Atrophy Type 4 (SMA4). Perez-Siles G, Ellis M, Ashe A, Grosz B, Vucic S, Kiernan MC, Morris KA, Reddel SW, Kennerson ML. Front Genet 12 801253 (2021)
  5. Calpain-1: a Novel Antiviral Host Factor Identified in Porcine Small Intestinal Mucus. Li Y, Wang X, Zhang E, Liu R, Yang C, Duan Y, Jiang Y, Yang Q. mBio 13 e0035822 (2022)
  6. An unexpected co-crystal structure of the calpain PEF(S) domain with Hfq reveals a potential chaperone function of Hfq. Cresser-Brown J, Rizkallah P, Jin Y, Roth C, Miller DJ, Allemann RK. Acta Crystallogr F Struct Biol Commun 76 81-85 (2020)
  7. Molecular signatures of Calpain 10 isoforms sequences, envisage functional similarity and therapeutic potential. Chaudhry B, Hanif F, Saboohi K. Pak J Pharm Sci 32 937-946 (2019)


Reviews citing this publication (5)

  1. The calpains: modular designs and functional diversity. Croall DE, Ersfeld K. Genome Biol 8 218 (2007)
  2. Structure-function relationships in calpains. Campbell RL, Davies PL. Biochem J 447 335-351 (2012)
  3. Mechanistic role of calpains in postischemic neurodegeneration. Bevers MB, Neumar RW. J Cereb Blood Flow Metab 28 655-673 (2008)
  4. The structural basis of calpain behavior. Benyamin Y. FEBS J 273 3413-3414 (2006)
  5. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future? Miller DJ, Adams SE, Hallett MB, Allemann RK. Future Med Chem 5 2057-2074 (2013)

Articles citing this publication (10)

  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 6 is involved in microtubule stabilization and cytoskeletal organization. Tonami K, Kurihara Y, Aburatani H, Uchijima Y, Asano T, Kurihara H. Mol Cell Biol 27 2548-2561 (2007)
  3. Characterization of the calpain/calpastatin system in human hemopoietic cell lines. Stifanese R, Averna M, Salamino F, Cantoni C, Mingari MC, Prato C, Pontremoli S, Melloni E. Arch Biochem Biophys 456 48-57 (2006)
  4. 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)
  5. Efficient expression and purification of recombinant human μ-calpain using an Escherichia coli expression system. Hata S, Kitamura F, Sorimachi H. Genes Cells 18 753-763 (2013)
  6. 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)
  7. Proteolysis of insulin-like growth factor binding proteins (IGFBPs) by calpain. Ghosh M, Shanker S, Siwanowicz I, Mann K, Machleidt W, Holak TA. Biol Chem 386 85-93 (2005)
  8. 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)
  9. Non-proteolytic calpain-6 interacts with VEGFA and promotes angiogenesis by increasing VEGF secretion. Oh M, Rho SB, Son C, Park K, Song SY. Sci Rep 9 15771 (2019)
  10. Detecting the active conformation of calpain with calpastatin-based reagents. Croall DE, Vanhooser LM, Cashon RE. Biochim Biophys Acta 1784 1676-1686 (2008)


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