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Originally published In Press as doi:10.1074/jbc.M105722200 on August 20, 2001

J. Biol. Chem., Vol. 276, Issue 43, 40133-40145, October 26, 2001
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A Membrane-proximal Basic Domain and Cysteine Cluster in the C-terminal Tail of CCR5 Constitute a Bipartite Motif Critical for Cell Surface Expression*

Sundararajan VenkatesanDagger §, Ana PetrovicDagger , Massimo Locati, Yong-Ou KimDagger , Drew Weissman||, and Philip M. Murphy

From the Dagger  Laboratory of Molecular Microbiology and  Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892 and the || Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania 19104

We examined the structural requirements for cell surface expression, signaling, and human immunodeficiency virus co-receptor activity for the chemokine receptor, CCR5. Serial C-terminal truncation of CCR5 resulted in progressive loss of cell surface expression; mutants truncated at the 317th position and shorter were not detected at the cell surface. Alanine substitution of basic residues in the membrane-proximal domain (residues 314-322) in the context of a full-length C-tail resulted in severe reduction in surface expression. C-terminal truncation that excised the three cysteines in this domain reduced surface expression, but further truncation of upstream basic residue(s) abolished surface expression. Substituting the carboxyl-terminal domain of CXCR4 for that of CCR5 failed to rectify the trafficking defect of the tailless CCR5. In contrast, tailless CXCR4 or a CXCR4 chimera that exchanged the native cytoplasmic domain for that of wild type CCR5 was expressed at the cell surface. Deletion mutants that expressed at the cell surface responded to chemokine stimulation and mediated human immunodeficiency virus entry. Substitution of all serine and threonine residues in the C-terminal tail of CCR5 abolished chemokine-mediated receptor phosphorylation but preserved downstream signaling (Ca2+ flux), while substitutions of tyrosine residues in the C-tail affected neither phenotype. CCR5 mutants that failed to traffic to the plasma membrane did not exhibit obvious changes in metabolic turnover and were retained in the Golgi or pre-Golgi compartments(s). Thus, the basic domain (-KHIAKRF-) and the cysteine cluster (-CKCC-) in the C-terminal tail of CCR5 function cooperatively for optimal surface expression.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: LMM, NIAID, Bldg. 10, Rm. 6A05, National Institutes of Health, Bethesda, MD 20892-1576. Tel.: 301-496-6359; Fax: 301-402-4122; E-mail: aradhana@helix.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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