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J. Biol. Chem., Vol. 281, Issue 28, 19395-19406, July 14, 2006

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A Structural Determinant of Human Cytomegalovirus US2 Dictates the Down-regulation of Class I Major Histocompatibility Molecules^*

Kristina Oresic, Vanessa Noriega¹, Laura Andrews, and Domenico Tortorella²

From the Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029 and the Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, 1000 Ljubljana, Slovenia

Human cytomegalovirus down-regulates cell surface class I major histocompatibility (MHC) molecules, thus allowing the virus to proliferate while avoiding detection by CD8⁺ T lymphocytes. The unique short gene product US2 is a 199-amino acid type I endoplasmic reticulum glycoprotein that modulates surface expression of class I MHC products by targeting class I heavy chains for dislocation from the endoplasmic reticulum to the cytosol, where they undergo proteasomal degradation. Although the mechanism by which this viral protein targets class I heavy chains for destruction remains unclear, the putative US2 cytoplasmic tail comprised of only 14 residues is known to play a functional role. To determine the specific residues critical for mediating class I degradation, a mutagenesis analysis of the cytoplasmic tail of US2 was performed. Using truncation mutants, the removal of only 4 residues (mutant US2₁₉₅) from the US2 carboxyl terminus completely abolishes class I destruction. Furthermore, site-directed mutagenesis of the US2 cytoplasmic tail revealed that the most critical residues for class I-induced destruction, cysteine 187, serine 190, tryptophan 193, and phenylalanine 196, occurs every third residue. This experimental data supports a model that the US2 cytoplasmic tail is in a3₁₀ helical configuration. Such a secondary structure would predict that one side of the 3₁₀ helical cytoplasmic tail would interact with the extraction apparatus to facilitate the dislocation and subsequent destruction of class I heavy chains.

Received for publication, February 2, 2006 , and in revised form, April 21, 2006.

^* This work was supported in part by National Institutes of Health Grant AI060905. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Pre-doctoral trainee and supported by United States Public Health Service Institutional Research Training Award AI07647.

² To whom correspondence should be addressed: One Gustave L. Levy Place, Box 1124, New York, NY 10029. Tel.: 212-241-5447; Fax: 212-241-7336; E-mail: Domenico.Tortorella{at}mssm.edu.

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