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J. Biol. Chem., Vol. 280, Issue 5, 3275-3285, February 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/5/3275    most recent M407536200v3 M407536200v2 M407536200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Casarosa, P. Articles by Leurs, R. Search for Related Content PubMed PubMed Citation Articles by Casarosa, P. Articles by Leurs, R. Social Bookmarking                      What's this?

CC and CX3C Chemokines Differentially Interact with the N Terminus of the Human Cytomegalovirus-encoded US28 Receptor^*

Paola Casarosa, Maria Waldhoer, Patricia J. LiWang¶, Henry F. Vischer¶¶, Thomas Kledal||, Henk Timmerman, Thue W. Schwartz**, Martine J. Smit||||, and Rob Leurs

From the Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, Ernest Gallo Research Center, University of California, San Francisco, California 94608, the ^¶Department of Biochemistry and Biophysics, Texas A&M University, Texas 77843, ^||Copenhagen University Hospital, Hvidovre 2650, Denmark, ^**Laboratory for Molecular Pharmacology, Panum Institute, University of Copenhagen, Copenhagen DK-2100, Denmark, and 7TM-Pharma A/, Fremtidsvej 3, Hørsholm DK-2970, Denmark

Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28, that displays homology to the human chemokine receptor CCR1 and binds several chemokines of the CC family as well as the CX3C chemokine fractalkine with high affinity. Most importantly, following HCMV infection, US28 activates several intracellular pathways, either constitutively or in a chemokine-dependent manner. In this study, our goal was to understand the molecular interactions between chemokines and the HCMV-encoded US28 receptor. To achieve this goal, a double approach has been used, consisting in the analysis of both receptor and ligand mutants. This approach has led us to identify several amino acids located in the N terminus of US28 that differentially contribute to the high affinity binding of CC versus CX3C chemokines. Additionally, our results highlight the importance of secondary modifications occurring at US28, such as sulfation, for ligand recognition. Finally, the effects of chemokine dimerization and interaction with glycosaminoglycans (GAGs) on chemokine binding and activation of US28 were investigated as well using CCL4 as model ligand. In line with the two-state model describing chemokine/receptor interaction, we show that an aromatic residue in the N-loop region of CCL4 promotes tight binding to US28, whereas receptor activation depends on the presence of the N terminus of CCL4, as shown previously for CCR5.

Received for publication, July 6, 2004 , and in revised form, November 8, 2004.

^* 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.

Supported by Altana Nederland B. V. (Zwanenburg, The Netherlands).

^¶¶ Supported by the Technology Foundation (STW).

^|||| Supported by the Royal Netherlands Academy of Arts and Sciences.

To whom correspondence should be addressed: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Tel.: 31-20-4447579; Fax: 31-20-4447610; E-mail: leurs{at}few.vu.nl.

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