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Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase
Calcium (Ca(2+)) signaling plays an important role in the regulation of many cellular functions. Ca(2+)-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca(2+)/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. H...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9806222/ https://www.ncbi.nlm.nih.gov/pubmed/36601586 http://dx.doi.org/10.3389/fmolb.2022.1104942 |
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author | Li, Xiaolong Li, Bo Li, Jun Yang, Mingyuan Bai, Yushu Chen, Kai Chen, Ziqiang Mao, Ningfang |
author_facet | Li, Xiaolong Li, Bo Li, Jun Yang, Mingyuan Bai, Yushu Chen, Kai Chen, Ziqiang Mao, Ningfang |
author_sort | Li, Xiaolong |
collection | PubMed |
description | Calcium (Ca(2+)) signaling plays an important role in the regulation of many cellular functions. Ca(2+)-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca(2+)/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca(2+) on the conformational dynamics of the DAPK1−CaM interactions is still unclear. Here, we performed large-scale molecular dynamics (MD) simulations of the DAPK1−CaM complex in the Ca(2+)-bound and-unbound states to reveal the importance of Ca(2+). MD simulations revealed that removal of Ca(2+) increased the anti-correlated inter-domain motions between DAPK1 and CaM, which weakened the DAPK1−CaM interactions. Binding free energy calculations validated the decreased DAPK1−CaM interactions in the Ca(2+)-unbound state. Structural analysis further revealed that Ca(2+) removal caused the significant conformational changes at the DAPK1−CaM interface, especially the helices α1, α2, α4, α6, and α7 from the CaM and the basic loop and the phosphate-binding loop from the DAPK1. These results may be useful to understand the biological role of Ca(2+) in physiological processes. |
format | Online Article Text |
id | pubmed-9806222 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98062222023-01-03 Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase Li, Xiaolong Li, Bo Li, Jun Yang, Mingyuan Bai, Yushu Chen, Kai Chen, Ziqiang Mao, Ningfang Front Mol Biosci Molecular Biosciences Calcium (Ca(2+)) signaling plays an important role in the regulation of many cellular functions. Ca(2+)-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca(2+)/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca(2+) on the conformational dynamics of the DAPK1−CaM interactions is still unclear. Here, we performed large-scale molecular dynamics (MD) simulations of the DAPK1−CaM complex in the Ca(2+)-bound and-unbound states to reveal the importance of Ca(2+). MD simulations revealed that removal of Ca(2+) increased the anti-correlated inter-domain motions between DAPK1 and CaM, which weakened the DAPK1−CaM interactions. Binding free energy calculations validated the decreased DAPK1−CaM interactions in the Ca(2+)-unbound state. Structural analysis further revealed that Ca(2+) removal caused the significant conformational changes at the DAPK1−CaM interface, especially the helices α1, α2, α4, α6, and α7 from the CaM and the basic loop and the phosphate-binding loop from the DAPK1. These results may be useful to understand the biological role of Ca(2+) in physiological processes. Frontiers Media S.A. 2022-12-19 /pmc/articles/PMC9806222/ /pubmed/36601586 http://dx.doi.org/10.3389/fmolb.2022.1104942 Text en Copyright © 2022 Li, Li, Li, Yang, Bai, Chen, Chen and Mao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Li, Xiaolong Li, Bo Li, Jun Yang, Mingyuan Bai, Yushu Chen, Kai Chen, Ziqiang Mao, Ningfang Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title | Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title_full | Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title_fullStr | Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title_full_unstemmed | Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title_short | Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
title_sort | mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9806222/ https://www.ncbi.nlm.nih.gov/pubmed/36601586 http://dx.doi.org/10.3389/fmolb.2022.1104942 |
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