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J. Biol. Chem., Vol. 281, Issue 48, 36652-36661, December 1, 2006

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Structure/Function Relationships of CCR8 Agonists and Antagonists

AMINO-TERMINAL EXTENSION OF CCL1 BY A SINGLE AMINO ACID GENERATES A PARTIAL AGONIST^*

James M. Fox, Pilar Najarro, Geoffrey L. Smith¹, Sofie Struyf^¶2, Paul Proost^¶2, and James E. Pease³

From the Leukocyte Biology Section, National Heart and Lung Institute Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom, the Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, London W2 1PG, United Kingdom, and the ^¶Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

We describe here the interactions of CCR8 with its ligands using both CCR8 transfectants and a T-cell line expressing the receptor endogenously. Of the CCR8 agonists reported previously, only CCL1 and vMIP-I exhibited potency in assays of intracellular calcium flux, chemotaxis, and receptor internalization, this latter mechanism being dependent upon the expression of -arrestins 1 and 2 but independent of G_i signaling. NH₂-terminal extension of the mature CCL1 sequence by a serine residue (Ser-CCL1) resulted in a partial agonist with a reduced affinity for CCR8, suggesting that the NH₂ terminus of the ligand plays a role in ligand binding to an intrahelical site. Attempts to identify key residues within this site revealed that the conserved glutamic acid residue in transmembrane helix 7, Glu-286, is crucial for trafficking of the receptor to the cell surface, while Asp-97 of transmembrane helix 2 is dispensable. CCL7 was found to inhibit both Ser-CCL1 and vMIP-I responses but not those of CCL1 itself. Similarly, vMIP-I responses were more than 2 orders of magnitude more sensitive to the specific CCR8 antagonist MC148 than those induced by CCL1, which is difficult to reconcile with the reported affinities for the receptor. Collectively, these data suggest that the CCR8 ligands are allotropic, binding to distinct sites within CCR8 and that the human immune system may have evolved to use CCL7 as a selective antagonist of viral chemokine activity at CCR8 but not those of the host ligand.

Received for publication, June 12, 2006 , and in revised form, September 25, 2006.

^* This work was supported in part by the Medical Research Council (to J. M. F. and J. E. P.), the Wellcome Trust (to P. N.), and European Union 6FP EC Contract INNOCHEM (to S. S. and P. P.). 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 A Wellcome Trust Principal Research Fellow.

² These two authors are senior research assistants of the F.W.O.-Vlaanderen.

³ To whom correspondence should be addressed: Leukocyte Biology Section, National Heart and Lung Institute, South Kensington Campus, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Bldg., London SW7 2AZ, UK. Tel.: 44-20-7594-3162; Fax: 44-20-7594-3119; E-mail: j.pease{at}imperial.ac.uk.

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