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Journal of Virology, January 2004, p. 413-423, Vol. 78, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.1.413-423.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Structural and Functional Analysis of Human Cytomegalovirus US3 Protein

Shahram Misaghi,1,{dagger} Zhen-Yu J. Sun,2,{dagger} Patrick Stern,1 Rachelle Gaudet,3 Gerhard Wagner,2 and Hidde Ploegh1*

Department of Pathology,1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,2 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 021383

Received 28 July 2003/ Accepted 22 September 2003

Human cytomegalovirus (HCMV) unique short region 3 (US3) protein, a type I membrane protein, prevents maturation of class I major histocompatibility complex (MHC) molecules by retaining them in the endoplasmic reticulum (ER) and thus helps inhibit antigen presentation to cytotoxic T cells. US3 molecules bind to class I MHC molecules in a transient fashion but retain them very efficiently in the ER nonetheless. The US3 luminal domain is responsible for ER retention of US3 itself, while both the US3 luminal and transmembrane domains are necessary for retaining class I MHC in the ER. We have expressed the luminal domain of US3 molecule in Escherichia coli and analyzed its secondary structure by using nuclear magnetic resonance. We then predicted the US3 tertiary structure by modeling it based on the US2 structure. Unlike the luminal domain of US2, the US3 luminal domain does not obviously interact with class I MHC molecules. The luminal domain of US3 dynamically oligomerizes in vitro and full-length US3 molecules associate with each other in vivo. We present a model depicting how dynamic oligomerization of US3 may enhance its ability to retain class I molecules within the ER.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 432-4777. Fax: (617) 432-4775. E-mail: hidde_ploegh{at}hms.harvard.edu.

{dagger} S.M. and Z.-Y.J.S. contributed equally to this study.

Journal of Virology, January 2004, p. 413-423, Vol. 78, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.1.413-423.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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