Mechanistic Insights into the Role of Calcium in the Allosteric Regulation of the Calmodulin-regulated Death-associated Protein Kinase

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2023 Jan 5

PMID 36601586

Authors

Xiaolong Li

Bo Li

Jun Li

Mingyuan Yang

Yushu Bai

Kai Chen

Ziqiang Chen

Ningfang Mao

Affiliations

Soon will be listed here.

Abstract

Calcium (Ca) signaling plays an important role in the regulation of many cellular functions. Ca-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca 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-bound and-unbound states to reveal the importance of Ca. MD simulations revealed that removal of Ca 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-unbound state. Structural analysis further revealed that Ca 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 in physiological processes.

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