Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation

Ming S Liu, Die Wang, Hiroyuki Morimoto, Howard Chi Ho Yim, Aaron Trent Irving, Bryan Raymond George Williams, Anthony John Sadler

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1 Citation (Scopus)

Abstract

A key control point in gene expression is the initiation of protein translation, with a universal stress response being constituted by inhibitory phosphorylation of the eukaryotic initiation factor 2alpha (eIF2alpha). In humans, four kinases sense diverse physiological stresses to regulate eIF2alpha to control cell differentiation, adaptation, and survival. Here we develop a computational molecular model of eIF2alpha and one of its kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions generated by coarse-grained dynamics simulations suggest a novel mode of action. Experimentation substantiates these predictions, identifying a previously unrecognized interface in the protein complex, which is constituted by dynamic residues in both eIF2alpha and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the eIF2alpha kinases and demonstrate the value of conducting computational analysis to evaluate protein function.
Original languageEnglish
Pages (from-to)473 - 485
Number of pages13
JournalJournal of Molecular Cell Biology
Volume6
Issue number6
DOIs
Publication statusPublished - 2014

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