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Volume 272, Number 37, Issue of September 12, 1997 pp. 23186-23190
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Amino-terminal Domain of CCR2 Is Both Necessary and Sufficient for High Affinity Binding of Monocyte Chemoattractant Protein 1
RECEPTOR ACTIVATION BY A PSEUDO-TETHERED LIGAND

(Received for publication, July 7, 1997)

Felipe S. Monteclaro ^§ and Israel F. Charo ^§¶

From the  Gladstone Institute of Cardiovascular Disease, the ^¶ Department of Medicine, the  Daiichi Research Center, and the ^§ Cardiovascular Research Institute, University of California, San Francisco, California 94141-9100

High affinity binding of monocyte chemoattractant protein 1 (MCP-1) requires the presence of the amino-terminal domain of CCR2, the MCP-1 receptor. Here we report that the 35 amino-terminal residues of CCR2, expressed as a membrane-bound fusion protein, bound MCP-1 with an affinity similar to that of the intact, wild-type receptor. Furthermore, the amino-terminal fusion protein enhanced, in trans, agonist-dependent activation of a CCR2 variant that was engineered to lack the high affinity binding sites for MCP-1. Mutation of highly conserved cysteines in the amino-terminal domain and third extracellular loop of CCR2, but not in the fusion protein, resulted in a dramatic loss of MCP-1 binding, suggesting the existence of a critical intramolecular disulfide bond that positions the amino-terminal protein for ligand interaction. These data indicate that the amino-terminal region of CCR2 is both necessary and sufficient for the high affinity binding of MCP-1 and provide the first direct evidence for activation of a chemokine receptor by a pseudo-tethered ligand. In this model, high affinity binding by the relatively short amino-terminal domain of CCR2 serves to tether MCP-1 and enhance low affinity interactions with distal regions of the receptor.

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