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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...

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Autores principales: Li, Xiaolong, Li, Bo, Li, Jun, Yang, Mingyuan, Bai, Yushu, Chen, Kai, Chen, Ziqiang, Mao, Ningfang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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.
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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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