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* Department of Experimental Medicine, University of Genoa, Genoa;
Department of Biochemical Sciences and
Istituto Pasteur Fondazione Cenci Bolognetti, University "La Sapienza", Rome;
Department of Experimental Oncology, Molecular Therapy Unit, Istituto Nazionale Tumori, Milan; and
¶ Department of Biomolecular Sciences and Biotechnology and Consiglio Nazionale delle Ricerche–Istituto Nazionale per la Fisica della Materia, University of Milan, Milan, Italy
UL18 is a glycoprotein encoded by the human cytomegalovirus genome and is thought to play a pivotal role during human cytomegalovirus infection, although its exact function is still a matter of debate. UL18 shares structural similarity with MHC class I and binds the receptor CD85j on immune cells. Besides UL18, CD85j binds MHC class I molecules. The binding properties of CD85j to MHC class I molecules have been thoroughly studied. Conversely, very little information is available on the CD85j/UL18 complex, namely that UL18 binds CD85j through its 
3 domain with an affinity that is 
1000-fold higher than the MHC class I affinity for CD85j. Deeper knowledge of features of the UL18/CD85j complex would help to disclose the function of UL18 when it binds to CD85j. In this study we first demonstrated that the UL183 domain is not sufficient per se for binding and that β2-microglobulin is necessary for UL18–CD85j interaction. We then dissected structural determinants of binding UL18 to CD85j. To this end, we constructed a three-dimensional model of the complex. The model was used to design mutants in selected regions of the putative interaction interface, the effects of which were measured on binding. Six regions in both the 2 and 3 domains and specific amino acids within them were identified that are potentially involved in the UL18–CD85j interaction. The higher affinity of UL18 to CD85j, compared with MHC class I, seems to be due not to additional interaction regions but to an overall better fit of the two molecules.
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.
1 This work was supported by grants from Fondazione Compagnia di San Paolo, Ministero per l’Istruzione, l’Università e la Ricerca Scientifica, and Progetto Finalizzato Ministero della Salute (to E.C.), and was partially supported by the European Commission within its FP6 Programme contract number LSHG-CT-2003-503265, and by the Istituto Pasteur Fondazione Cenci Bolognetti (to A.T.).
2 M.O. and F.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Fabio Ghiotto, Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genoa, Italy. E-mail address: fghiotto{at}unige.it
4 Abbreviations used in this paper: HCMV, human cytomegalovirus; β2m, β2-microglobulin; PDB, Brookhaven Protein Data Bank.
5 The online version of this article contains supplemental material.
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