Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 2005 Sep 23;122(6):901-13
Date
09/24/2005Pubmed ID
16179259DOI
10.1016/j.cell.2005.06.041Scopus ID
2-s2.0-25144477805 (requires institutional sign-in at Scopus site) 309 CitationsAbstract
The antiviral protein kinase PKR inhibits protein synthesis by phosphorylating the translation initiation factor eIF2alpha on Ser51. Binding of double-stranded RNA to the regulatory domains of PKR promotes dimerization, autophosphorylation, and the functional activation of the kinase. Herein, we identify mutations that activate PKR in the absence of its regulatory domains and map the mutations to a recently identified dimerization surface on the kinase catalytic domain. Mutations of other residues on this surface block PKR autophosphorylation and eIF2alpha phosphorylation, while mutating Thr446, an autophosphorylation site within the catalytic-domain activation segment, impairs eIF2alpha phosphorylation and viral pseudosubstrate binding. Mutational analysis of catalytic-domain residues preferentially conserved in the eIF2alpha kinase family identifies helix alphaG as critical for the specific recognition of eIF2alpha. We propose an ordered mechanism of PKR activation in which catalytic-domain dimerization triggers Thr446 autophosphorylation and specific eIF2alpha substrate recognition.
Author List
Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, Dever TEAuthor
Madhusudan Dey PhD Assistant Professor in the Biological Sciences department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
CatalysisDimerization
Eukaryotic Initiation Factor-2
Mutagenesis, Site-Directed
Phosphorylation
Protein Binding
Protein Conformation
Protein Structure, Secondary
RNA, Double-Stranded
Saccharomyces cerevisiae
eIF-2 Kinase
