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Joma Joy, Narasimharao Nalabothula, Madhumita Ghosh, Oliver Popp, Marianne Jochum, Werner Machleidt, Shirley Gil-Parrado, Tad A. Holak

Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19^INK4d

Keywords: calpain, calpastatin, cyclin-dependent kinases, nuclear magnetic resonance spectroscopy, proteolysis, p19INK4d

Calpains are a large family of Ca²⁺-dependent cysteine proteases that are ubiquitously distributed across most cell types and vertebrate species. Calpains play a role in cell differentiation, apoptosis, cytoskeletal remodeling, signal transduction and the cell cycle. The cell cycle proteins cyclin D1 and p21^KIP1, for example, have been shown to be affected by calpains. However, the rules that govern calpain cleavage specificity are poorly understood. We report here studies on the pattern of ?-calpain proteolysis of the p19^INK4d protein, a cyclin-dependent kinase 4/6 inhibitor that negatively regulates the mammalian cell cycle. Our data show new characteristics of calpain action: ?-calpain cleaves p19^INK4d immediately after the first and second ankyrin repeats that are structurally less stable compared to the other repeats. This is in contrast to features observed so far in the specificity of calpains for their substrates. These results imply that calpain may be involved in the cell cycle by regulating the cell cycle regulatory protein turnover through CDK inhibitors and cyclins.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 387, 03/2006
Pages: 329 - 335

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