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Requirement for Serine-384 in Caspase-2 processing and activity
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532978/ https://www.ncbi.nlm.nih.gov/pubmed/33011746 http://dx.doi.org/10.1038/s41419-020-03023-6 |
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author | Zamaraev, Alexey V. Volik, Pavel I. Nilov, Dmitry K. Turkina, Maria V. Egorshina, Aleksandra Yu. Gorbunova, Anna S. Iarovenko, Svetlana Iu. Zhivotovsky, Boris Kopeina, Gelina S. |
author_facet | Zamaraev, Alexey V. Volik, Pavel I. Nilov, Dmitry K. Turkina, Maria V. Egorshina, Aleksandra Yu. Gorbunova, Anna S. Iarovenko, Svetlana Iu. Zhivotovsky, Boris Kopeina, Gelina S. |
author_sort | Zamaraev, Alexey V. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7532978 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75329782020-10-19 Requirement for Serine-384 in Caspase-2 processing and activity Zamaraev, Alexey V. Volik, Pavel I. Nilov, Dmitry K. Turkina, Maria V. Egorshina, Aleksandra Yu. Gorbunova, Anna S. Iarovenko, Svetlana Iu. Zhivotovsky, Boris Kopeina, Gelina S. Cell Death Dis Article 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. Nature Publishing Group UK 2020-10-03 /pmc/articles/PMC7532978/ /pubmed/33011746 http://dx.doi.org/10.1038/s41419-020-03023-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zamaraev, Alexey V. Volik, Pavel I. Nilov, Dmitry K. Turkina, Maria V. Egorshina, Aleksandra Yu. Gorbunova, Anna S. Iarovenko, Svetlana Iu. Zhivotovsky, Boris Kopeina, Gelina S. Requirement for Serine-384 in Caspase-2 processing and activity |
title | Requirement for Serine-384 in Caspase-2 processing and activity |
title_full | Requirement for Serine-384 in Caspase-2 processing and activity |
title_fullStr | Requirement for Serine-384 in Caspase-2 processing and activity |
title_full_unstemmed | Requirement for Serine-384 in Caspase-2 processing and activity |
title_short | Requirement for Serine-384 in Caspase-2 processing and activity |
title_sort | requirement for serine-384 in caspase-2 processing and activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532978/ https://www.ncbi.nlm.nih.gov/pubmed/33011746 http://dx.doi.org/10.1038/s41419-020-03023-6 |
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