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, 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 alpha 1, alpha 2, alpha 4, alpha 6, and alpha 7 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.

Automated summary

Calcium (Ca2+) signaling plays a crucial role in cellular functions, and the binding of Ca2+/CaM to DAPK1 regulates intracellular signaling pathways. This study used molecular dynamics simulations to reveal the importance of Ca2+ in the conformational dynamics of DAPK1-CaM interactions. The results showed that removal of Ca2+ weakened the interactions between DAPK1 and CaM and caused significant conformational changes at the DAPK1-CaM interface.