title: Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation.
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 2α (eIF2α). In humans, four kinases sense diverse physiological stresses to regulate eIF2α to control cell differentiation, adaptation, and survival. Here we develop a computational molecular model of eIF2α 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 eIF2α and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the eIF2α kinases and demonstrate the value of conducting computational analysis to evaluate protein function.
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia CSIRO - Computational Informatics and Digital Productivity Flagship, Private Bag 10, Clayton South, VIC 3169, Australia anthony.sadler@mimr-phi.org ming.liu@csiro.au.
authors.forename: Ming S
authors.initials: MS
authors.lastname: Liu
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia.
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morimoto
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia.
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Yim
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Irving
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia Department of Molecular and Translational Science, Monash University, Melbourne, VIC 3168, Australia.
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, VIC 3168, Australia Department of Molecular and Translational Science, Monash University, Melbourne, VIC 3168, Australia anthony.sadler@mimr-phi.org ming.liu@csiro.au.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sadler
mesh_terms: D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D014176:Protein Biosynthesis / Q000502:physiology*; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase
keywords: eIF2α kinases; eukaryotic initiation factor 2α (eIF2α); kinase activity; molecular dynamics; protein kinase R (PKR); protein translation