NDLI: The TXP Motif in the Second Transmembrane Helix of CCR5 A STRUCTURAL DETERMINANT OF CHEMOKINE-INDUCED ACTIVATION

Content Provider	Journal of Biological Chemistry (JBC)
Author	Govaerts, Cédric Blanpain, Cédric Deupi, Xavier Ballet, Sébastien Ballesteros, Juan A. Wodak, Shoshana J. Vassart, Gilbert Pardo, Leonardo Parmentier, Marc
Abstract	CCR5 is a G-protein-coupled receptor activated by the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein 1α and 1β, and monocyte chemotactic protein 2 and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have identified a sequence motif (TXP) in the second transmembrane helix of chemokine receptors and investigated its role by theoretical and experimental approaches. Molecular dynamics simulations of model α-helices in a nonpolar environment were used to show that a TXP motif strongly bends these helices, due to the coordinated action of the proline, which kinks the helix, and of the threonine, which further accentuates this structural deformation. Site-directed mutagenesis of the corresponding Pro and Thr residues in CCR5 allowed us to probe the consequences of these structural findings in the context of the whole receptor. The P84A mutation leads to a decreased binding affinity for chemokines and nearly abolishes the functional response of the receptor. In contrast, mutation of Thr-822.56 into Val, Ala, Cys, or Ser does not affect chemokine binding. However, the functional response was found to depend strongly on the nature of the substituted side chain. The rank order of impairment of receptor activation is P84A > T82V > T82A > T82C > T82S. This ranking of impairment parallels the bending of the α-helix observed in the molecular simulation study.
Related Links	http://www.jbc.org/content/276/16/13217.abstract
Ending Page	13225
Starting Page	13217
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	16
Volume Number	276
DOI	10.1074/jbc.M011670200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2001-04-20
Access Restriction	Open
Subject Keyword	G-protein-coupled receptor (GPCR) Human immunodeficiency virus (HIV) Transmembrane helix (TM) Proline kink (PK) Molecular dynamics (MD) Macrophage inflammatory protein (MIP) Monocyte chemotactic protein (MCP) Wild type (WT) Regulated on activation normal T cell expressed and secreted (RANTES) PROTEIN STRUCTURE AND FOLDING
Alternative Title	The TXP Motif in the Second Transmembrane Helix of CCR5
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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