The effect of phosphorylation on the conformational dynamics and allostery of the association of death-associated protein kinase with calmodulin

Abstract

Protein phosphorylation plays an important role in the signal transduction and is capable of regulation of cell activity. The death-associated protein kinase 1 (DAPK1), as a Ser/Thr kinase, interacts with calmodulin (CaM) to regulate apoptotic and autophagic signaling. Autophosphorylation of DAPK1 at Ser308 located at the autoregulatory domain (ARD) blocks CaM binding and inhibits kinase catalytic activity. However, the mechanism underlying the influence of Ser308 phosphorylation (pS308) on the DAPK1 activity remains unclear. Here, we performed multiple, microsecond length molecular dynamics (MD) simulations, the molecular mechanics generalized Born/surface area (MM-GBSA) binding free energy calculations, principal component analysis, and dynamic cross-correlation analysis to unravel the conformational dynamics and allostery of the DAPK1 − CaM interaction triggered by the pS308 at the ARD. MD simulations showed that pS308 affected the conformational stability of the DAPK1 − CaM complex. Further energetic and structural exploration revealed that pS308 weakened the association of the phosphorylated DAPK1 to CaM, which lowered the susceptibility of DAPK1 to be activated by CaM. This result can provide mechanistic insights into the molecular underpinning through which the DAPK1 kinase activity is modulated by the auto-phosphorylation.

Communicated by Ramaswamy H. Sarma

Keywords:

• DAPK1
• calmodulin
• molecular dynamics simulations
• MM-GBSA
• protein phosphorylation

Disclosure statement

The authors declare no competing financial interest.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.