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PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Mol Cell Biol 2005 Apr;25(8):3063-75

Date

03/31/2005

Pubmed ID

15798194

Pubmed Central ID

PMC1069625

DOI

10.1128/MCB.25.8.3063-3075.2005

Scopus ID

2-s2.0-20144386673 (requires institutional sign-in at Scopus site)   62 Citations

Abstract

Four stress-responsive protein kinases, including GCN2 and PKR, phosphorylate eukaryotic translation initiation factor 2alpha (eIF2alpha) on Ser51 to regulate general and gene-specific protein synthesis. Phosphorylated eIF2 is an inhibitor of its guanine nucleotide exchange factor, eIF2B. Mutations that block translational regulation were isolated throughout the N-terminal OB-fold domain in Saccharomyces cerevisiae eIF2alpha, including those at residues flanking Ser51 and around 20 A away in the conserved motif K79GYID83. Any mutation at Glu49 or Asp83 blocked translational regulation; however, only a subset of these mutations impaired Ser51 phosphorylation. Substitution of Ala for Asp83 eliminated phosphorylation by GCN2 and PKR both in vivo and in vitro, establishing the critical contributions of remote residues to kinase-substrate recognition. In contrast, mutations that blocked translational regulation but not Ser51 phosphorylation impaired the binding of eIF2B to phosphorylated eIF2alpha. Thus, two structurally distinct effectors of eIF2 function, eIF2alpha kinases and eIF2B, have evolved to recognize the same surface and overlapping determinants on eIF2alpha.

Author List

Dey M, Trieselmann B, Locke EG, Lu J, Cao C, Dar AC, Krishnamoorthy T, Dong J, Sicheri F, Dever TE

Author

Madhusudan Dey PhD Assistant Professor in the Biological Sciences department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Amino Acid Substitution
Conserved Sequence
DNA Mutational Analysis
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factor-2B
Molecular Sequence Data
Mutation
Peptide Chain Initiation, Translational
Phosphorylation
Protein Conformation
Protein Kinases
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Serine
eIF-2 Kinase