An eIF2?-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2?.

Transient protein synthesis inhibition, mediated by phosphorylation of the ? subunit of eukaryotic translation initiation factor 2 (eIF2?), is an important protective mechanism cells use during stress conditions. Following relief of the stress, the growth arrest and DNA damage-inducible protein GADD34 associates with the broadly acting serine/threonine protein phosphatase 1 ...
(PP1) to dephosphorylate eIF2?. Whereas the PP1-binding motif on GADD34 has been defined, it remains to be determined how GADD34 directs PP1 to specifically dephosphorylate eIF2?. In this report, we map a novel eIF2?-binding motif to the C terminus of GADD34 in a region distinct from where PP1 binds to GADD34. This motif is characterized by the consensus sequence Rx[Gnl]x(1-2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc], where capital letters are preferred and x is any residue. Point mutations altering the eIF2?-binding motif impair the ability of GADD34 to interact with eIF2?, promote eIF2? dephosphorylation, and suppress PKR toxicity in yeast. Interestingly, this eIF2?-docking motif is conserved among viral orthologs of GADD34, and is necessary for the proteins produced by African swine fever virus, Canarypox virus, and Herpes simplex virus to promote eIF2? dephosphorylation. Taken together, these data indicate that GADD34 and its viral orthologs direct specific dephosphorylation of eIF2? by interacting with both PP1 and eIF2? through independent binding motifs.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Binding Sites, Eukaryotic Initiation Factor-2, Humans, Immunoblotting, Molecular Sequence Data, Phosphorylation, Point Mutation, Protein Binding, Protein Phosphatase 1, Saccharomyces cerevisiae, Sequence Homology, Amino Acid
Proc Natl Acad Sci U S A
Date: Jul. 07, 2015
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