title: Auto-phosphorylation Represses Protein Kinase R Activity.
abstract: The central role of protein kinases in controlling disease processes has spurred efforts to develop pharmaceutical regulators of their activity. A rational strategy to achieve this end is to determine intrinsic auto-regulatory processes, then selectively target these different states of kinases to repress their activation. Here we investigate auto-regulation of the innate immune effector protein kinase R, which phosphorylates the eukaryotic initiation factor 2α to inhibit global protein translation. We demonstrate that protein kinase R activity is controlled by auto-inhibition via an intra-molecular interaction. Part of this mechanism of control had previously been reported, but was then controverted. We account for the discrepancy and extend our understanding of the auto-inhibitory mechanism by identifying that auto-inhibition is paradoxically instigated by incipient auto-phosphorylation. Phosphor-residues at the amino-terminus instigate an intra-molecular interaction that enlists both of the N-terminal RNA-binding motifs of the protein with separate surfaces of the C-terminal kinase domain, to co-operatively inhibit kinase activation. These findings identify an innovative mechanism to control kinase activity, providing insight for strategies to better regulate kinase activity.
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: de Weerd
authors.affiliation: Proteomics and Metabolomics Laboratory, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
authors.forename: Galina
authors.initials: G
authors.lastname: Polekhina
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia.
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sadler
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019892:eIF-2 Kinase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase