Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase
Calcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca2+/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However...
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1104942/full |
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| author | Xiaolong Li Bo Li Jun Li Mingyuan Yang Yushu Bai Kai Chen Ziqiang Chen Ningfang Mao |
| author_facet | Xiaolong Li Bo Li Jun Li Mingyuan Yang Yushu Bai Kai Chen Ziqiang Chen Ningfang Mao |
| author_sort | Xiaolong Li |
| collection | DOAJ |
| description | Calcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca2+/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca2+ 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 Ca2+-bound and-unbound states to reveal the importance of Ca2+. MD simulations revealed that removal of Ca2+ 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 Ca2+-unbound state. Structural analysis further revealed that Ca2+ 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 Ca2+ in physiological processes. |
| first_indexed | 2024-04-11T05:49:00Z |
| format | Article |
| id | doaj.art-88d22b99931a41568870db022177ba26 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-11T05:49:00Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-88d22b99931a41568870db022177ba262022-12-22T04:42:07ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-12-01910.3389/fmolb.2022.11049421104942Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinaseXiaolong Li0Bo Li1Jun Li2Mingyuan Yang3Yushu Bai4Kai Chen5Ziqiang Chen6Ningfang Mao7Department of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, ChinaCalcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca2+/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca2+ 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 Ca2+-bound and-unbound states to reveal the importance of Ca2+. MD simulations revealed that removal of Ca2+ 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 Ca2+-unbound state. Structural analysis further revealed that Ca2+ 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 Ca2+ in physiological processes.https://www.frontiersin.org/articles/10.3389/fmolb.2022.1104942/fullcalciumcalmodulindeath-associated protein kinaseallosterymolecular dynamics simulation |
| spellingShingle | Xiaolong Li Bo Li Jun Li Mingyuan Yang Yushu Bai Kai Chen Ziqiang Chen Ningfang Mao Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase Frontiers in Molecular Biosciences calcium calmodulin death-associated protein kinase allostery molecular dynamics simulation |
| 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 | calcium calmodulin death-associated protein kinase allostery molecular dynamics simulation |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1104942/full |
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