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Originally published In Press as doi:10.1074/jbc.M202312200 on June 4, 2002

J. Biol. Chem., Vol. 277, Issue 33, 29593-29599, August 16, 2002
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Specific Phosphorylation of Exogenous Protein and Peptide Substrates by the Human Cytomegalovirus UL97 Protein Kinase
IMPORTANCE OF THE P+5 POSITION*

Moon-Chang BaekDagger , Paula M. Krosky§, Zuwen He, and Donald M. Coen||

From the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

Human cytomegalovirus UL97 is an unusual protein kinase that can phosphorylate nucleoside analogs such as ganciclovir but whose specificity for exogenous protein substrates has remained unknown. We found that purified, recombinant glutathione S-transferase-UL97 fusion protein can phosphorylate histone H2B. Phosphorylation was abrogated by substitution of glutamine for a conserved lysine in subdomain II and inhibited by a new antiviral drug, maribavir. Sequencing and mass spectrometric analyses of purified 32P-labeled tryptic peptides of H2B revealed that the sites of phosphorylation were, in order of extent, Ser-38, Ser-87, Ser-6, Ser-112, and Ser-124. Phosphorylation of synthetic peptides containing these sites, analyzed using a new, chimeric gel system, correlated with their phosphorylation in H2B. Phosphorylation of the Ser-38 peptide by UL97 occurred on Ser-38 and was specifically sensitive to maribavir, whereas phosphorylation of this peptide by cAMP-dependent protein kinase occurred on Ser-36. The extent of phosphorylation was greatest with peptides containing an Arg or Lys residue 5 positions downstream (P+5) from the Ser. Substitution with Ala at this position essentially eliminated activity. These results identify exogenous protein and peptide substrates of UL97, reveal an unusual dependence on the P+5 position, and may abet discovery of new inhibitors of UL97 and human cytomegalovirus replication.

* This work was supported in part by National Institutes of Health Grant RO1 AI26077 (to D. M. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported in part by the Korean Science and Engineering Foundation. Present address: Div. of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.

§ Supported in part by NIH Grant T32 AI07245. Present address: Screening Technologies Branch, Developmental Therapeutics Program, NCI-Frederick, Frederick, MD 21702.

Present address: Gotham Networks, Acton, MA 01720.

|| To whom correspondence should be addressed: Dept. of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., Boston, MA 02115. Tel.: 617-432-1691; Fax: 617-432-3833; E-mail: Don_Coen@hms.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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