The gamma134.5 protein of herpes simplex virus 1 has the structural and functional attributes of a protein phosphatase 1 regulatory subunit and is present in a high molecular weight complex with the enzyme in infected cells.
The carboxyl-terminal domain of the gamma134.5 protein of the herpes simplex virus 1 binds to protein phosphatase 1alpha (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 gamma134.5 functionally substitutes for gamma134.5. This report shows that gamma134.5 and PP1 form a complex in the infected cells, that fractions containing this complex specifically dephosphorylate eIF-2alpha, and that both gamma134.5 and GADD34 proteins contain the amino acid sequence motif common to subunits of PP1 that is required for binding to the PP1 catalytic subunit. An oligopeptide containing this motif competes with gamma134.5 for binding to PP1. Substitution of Val193 and Phe195 in the PP1-binding motif abolished activity. These results suggest that the carboxyl-terminal domain of gamma134.5 protein has the structural and functional attributes of a subunit of PP1 specific for eIF-2alpha, that it has evolved to preclude shut-off of protein synthesis, and that GADD34 may have a similar function.
Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois 60637, USA.
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Gross
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Roizman
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054645:Protein Phosphatase 1; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*
D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1