Molecular Cloning and Functional Characterization of a Novel Human CC Chemokine Receptor (CCR5) for RANTES, MIP-1β, and MIP-1α

Carol J Raport,Jennifa Gosling,Vicki L Schweickart,Patrick W Gray,Israel F Charo

doi:10.1074/jbc.271.29.17161

Abstract

Chemokines affect leukocyte chemotactic and activation activities through specific G protein-coupled receptors. In an effort to map the closely linked CC chemokine receptor genes, we identified a novel chemokine receptor encoded 18 kilobase pairs downstream of the monocyte chemoattractant protein-1 (MCP-1) receptor (CCR2) gene on human chromosome 3p21. The deduced amino acid sequence of this novel receptor, designated CCR5, is most similar to CCR2B, sharing 71% identical residues. Transfected cells expressing the receptor bind RANTES (regulated on activation normal T cell expressed), MIP-1beta, and MIP-1alpha with high affinity and generate inositol phosphates in response to these chemokines. This same combination of chemokines has recently been shown to potently inhibit human immunodeficiency virus replication in human peripheral blood leukocytes (Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., and Lusso, P.(1995) Science 270, 1811-1815). CCR5 is expressed in lymphoid organs such as thymus and spleen, as well as in peripheral blood leukocytes, including macrophages and T cells, and is the first example of a human chemokine receptor that signals in response to MIP-1beta.

Highlights

Chemokines mediate the migration and activation of leukocytes at sites of inflammation
CCR1 is specific for MIP-1␣, RANTES, and MCP-3 [7,8,9]; CCR2A and CCR2B are alternatively spliced gene products which recognize both monocyte chemoattractant protein-1 (MCP-1) and MCP-3 (10 –12); CCR3 is expressed on eosinophils and recognizes eotaxin [13, 14]; and CCR4 is found on basophils and responds to MIP-1␣, RANTES, and MCP-1 [15]
In our efforts to further analyze the genetic linkage of these CC chemokine receptor genes, we have identified a novel G protein-coupled receptor on chromosome 3 with significant homology to this gene family

Summary

Introduction

Chemokines mediate the migration and activation of leukocytes at sites of inflammation. The genes for CCR1, CCR2, and the related sequence V28 [18] have been mapped to human chromosome 3p21 (8, 18 –20). Leukin; CCR, CC chemokine receptor; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; RANTES, regulated on activation normal T cell expressed; YAC, yeast artificial chromosome; kb, kilobase(s).

Results

Conclusion