Requirement for Serine-384 in Caspase-2 processing and activity
| Autor: | D. K. Nilov, Aleksandra Yu Egorshina, Anna S. Gorbunova, Gelina S. Kopeina, Maria V Turkina, Boris Zhivotovsky, Pavel I. Volik, Svetlana Iu Iarovenko, Alexey V. Zamaraev |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cell death
Cancer Research Cellbiologi In silico Immunology Caspase 2 Mutation Missense Apoptosis Adenocarcinoma medicine.disease_cause Article Serine Cellular and Molecular Neuroscience medicine Humans Binding site lcsh:QH573-671 Caspase Mutation Binding Sites biology Chemistry lcsh:Cytology Cell Biology Proteases Cysteine protease Caspase 9 Cell biology Cysteine Endopeptidases biology.protein Phosphorylation |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 10, Pp 1-13 (2020) |
| ISSN: | 2041-4889 |
| Popis: | Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network. Funding Agencies|Russian Science FoundationRussian Science Foundation (RSF) [17-75-20102]; Russian Foundation for Basic ResearchRussian Foundation for Basic Research (RFBR) [20-015-00157, 18-29-09005]; Stockholm Cancer Society [181301]; Swedish Cancer SocietySwedish Cancer Society [190345] |
| Databáze: | OpenAIRE |
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