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J Biol Chem, Vol. 274, Issue 45, 32055-32062, November 5, 1999

Role of the First Extracellular Loop in the Functional Activation of CCR2
THE FIRST EXTRACELLULAR LOOP CONTAINS DISTINCT DOMAINS NECESSARY FOR BOTH AGONIST BINDING AND TRANSMEMBRANE SIGNALING

Ki Hoon Han, Simone R. Green, Rajendra K. Tangirala, Seiya Tanaka, and Oswald Quehenberger

From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0682

The physiological cellular responses to monocyte chemoattractant protein-1 (MCP-1), a potent chemotactic and activating factor for mononuclear leukocytes, are mediated by specific binding to CCR2. The aim of this investigation is to identify receptor microdomains that are involved in high affinity agonist binding and receptor activation. The results from our functional studies in which we utilized neutralizing antisera against CCR2 are consistent with a multidomain binding model, previously proposed by others. The first extracellular loop was of particular interest, because in addition to a ligand-binding domain it contained also information for receptor activation, crucial for transmembrane signaling. Replacement of the first extracellular loop of CCR2 with the corresponding region of CCR1 decreased the MCP-1 binding affinity about 10-fold and prevented transmembrane signaling. A more detailed analysis by site-directed mutagenesis revealed that this receptor segment contains two distinct microdomains. The amino acid residues Asn104 and Glu105 are essential for high affinity agonist binding but are not involved in receptor activation. In contrast, the charged amino acid residue His100 does not contribute to ligand binding but is vital for receptor activation and initiation of transmembrane signaling. We hypothesize that the interaction of agonist with this residue initiates the conformational switch that allows the formation of the functional CCR2-G protein complex.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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