The γ134.5 protein of herpes simplex virus 1 has the structural and functional attributes of a protein phosphatase I regulatory subunit and is present in a high molecular weight complex with the enzyme in infected cells

The carboxyl-terminal domain of the gamma(1)34.5 protein of the herpes simplex virus 1 binds to protein phosphatase 1 alpha (PP1) and is required to prevent the shut-off of protein synthesis resulting from phosphorylation of the alpha subunit of eIF-2 by the double-stranded RNA-activated protein kinase. The corresponding domain of the conserved GADD34 protein homologous to gamma(1)34.5 functionally substitutes for y(1)34.5, This report shows that y(1)34.5 and PPI form a complex in the infected cells, that fractions containing this complex specifically dephosphorylate eIF-2 alpha, and that both gamma(1)34.5 and GADD34 proteins contain the amino acid sequence motif common to subunits of PPI that is required for binding to the PPI catalytic subunit, An oligopeptide containing this motif competes with gamma(1)34.5 for binding to PPI, Substitution of Val(193) and Phe(195) in the PPI-binding motif abolished activity. These results suggest that the carboxyl-terminal domain of gamma(1)34.5 protein has the structural and functional attributes of a subunit of PP1 specific for eIF-2 alpha, that it has evolved to preclude shut-off of protein synthesis, and that GADD34 may have a similar function.