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Journal of Virology, April 2001, p. 3666-3674, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3666-3674.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

AlaArg Motif in the Carboxyl Terminus of the gamma 134.5 Protein of Herpes Simplex Virus Type 1 Is Required for the Formation of a High-Molecular-Weight Complex That Dephosphorylates eIF-2alpha

Guofeng Cheng,1 Martin Gross,2 Marie-Elena Brett,1 and Bin He1,*

Department of Microbiology and Immunology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois 60612,1 and Department of Pathology, The University of Chicago, Chicago, Illinois 606372

Received 1 December 2000/Accepted 25 January 2001

The gamma 134.5 protein of herpes simplex virus (HSV) type 1 functions to prevent the shutoff of protein synthesis mediated by the double-stranded-RNA-dependent protein kinase PKR. This is because gamma 134.5 associates with protein phosphatase 1 (PP1) through its carboxyl terminus, forming a high-molecular-weight complex that dephosphorylates the alpha  subunit of translation initiation factor eIF-2 (eIF-2alpha ). Here we show that Val193Glu and Phe195Leu substitutions in the PP1 signature motif of the gamma 134.5 protein abolished its ability to redirect PP1 to dephosphorylate eIF-2alpha and replication of mutant viruses was severely impaired. The gamma 134.5 protein, when expressed in Sf9 cells using a recombinant baculovirus, was capable of directing specific eIF-2alpha dephosphorylation. Deletions of amino acids 258 to 263 had no effect on activity of gamma 134.5. However, deletions of amino acids 238 to 258 abolished eIF-2alpha phosphatase activity but not PP1 binding activity. Interestingly, deletions in the AlaArg motif of the carboxyl terminus disrupted the high-molecular-weight complex that is required for dephosphorylation of eIF-2alpha . These results demonstrate that gamma 134.5 is functionally active in the absence of any other HSV proteins. In addition to a PP1 binding domain, the carboxyl terminus of gamma 134.5 contains an effector domain that is required to form a functional complex.

* Corresponding author. Mailing address: Department of Microbiology and Immunology (M/C 790), College of Medicine, The University of Illinois at Chicago, 835 South Wolcott Ave., Chicago, IL 60612. Phone: (312) 996-2391. Fax: (312) 996-6415. E-mail: tshuo{at}uic.edu.

Journal of Virology, April 2001, p. 3666-3674, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3666-3674.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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