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J. Biol. Chem., Vol. 283, Issue 7, 4031-4043, February 15, 2008

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A Bipartite Trigger for Dislocation Directs the Proteasomal Degradation of an Endoplasmic Reticulum Membrane Glycoprotein^*

From the Mount Sinai School of Medicine, Department of Microbiology, New York, New York 10029

Polypeptides are organized into distinct substructures, termed protein domains, that are often associated with diverse functions. These modular units can act as binding sites, areas of post-translational modification, and sites of complex multimerization. The human cytomegalovirus US2 gene product is organized into discrete domains that together catalyze the proteasome-dependent degradation of class I major histocompatibility complex heavy chains. US2 co-opts the endogenous ER quality control pathway in order to dispose of class I. The US2 endoplasmic reticulum (ER)-lumenal region is the class I binding domain, whereas the carboxyl terminus can be referred to as the degradation domain. In the present study, we examined the role of the US2 transmembrane domain in virus-mediated class I degradation. Replacement of the US2 transmembrane domain with that of the CD4 glycoprotein completely blocked the ability of US2 to induce class I destruction. A more precise mutagenesis revealed that subregions of the US2 transmembrane domain differ in their ability to trigger class I degradation. Collectively, the data support a model in which US2-mediated class I degradation occurs as a highly regulated process where the US2 transmembrane domain and cytoplasmic tail work in concert to eliminate class I molecules. Host factors, including a signal peptidase complex, probably associate with the US2 molecule in a coordinated fashion to create a predislocation complex to promote the extraction of class I out of the ER. The results imply that the ER quality control machinery may recognize and eliminate misfolded proteins using a similar multistep regulated process.

Received for publication, July 31, 2007 , and in revised form, December 14, 2007.

^* These studies were supported in part by United States Public Health Service Institutional Research Training Award AI07647 and 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 A predoctoral trainee, supported by National Institutes of Health Grant AI060905-SI.

² To whom correspondence should be addressed: Dept. of Microbiology, Mount Sinai School of Medicine, 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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