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(Journal of Leukocyte Biology. 2001;69:977-985.)
© 2001 by Society for Leukocyte Biology

A chimeric MIP-1/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors

Cédric Blanpain^*, Raphaële Buser, Christine A. Power, Michael Edgerton, Catherine Buchanan, Matthias Mack, Graham Simmons, Paul R. Clapham, Marc Parmentier^* and Amanda E. I. Proudfoot

^* IRIBHN Université Libre de Bruxelles, Campus Erasme, Bruxelles, Belgium;
Serono Pharmaceutical Research Institute, Geneva, Switzerland;
Medizinische Poliklinik, Ludwig-Maximilians-Univerity of Munich, Munich, Germany; and
The Wohl Virion Centre, Department of Molecular Pathology, The Windeyer Institute for Medical Sciences, University College Medical School, London, UK

Correspondence: Amanda E. I. Proudfoot, Serono Pharmaceutical Research Institute, 14, Chemin des Aulx, 1228 Plan les Ouates, Geneva, Switzerland. E-mail: amanda.proudfoot{at}serono.com

Human RANTES (CCL5) and MIP-1 (CCL3) bind and activate several CC chemokine receptors. RANTES is a high-affinity ligand for CCR1 and CCR5, and it binds CCR3 with moderate affinity and CCR4 with low affinity. MIP-1 has similar binding characteristics to RANTES except that it does not bind to CCR3. Here we have generated a chimera of human MIP-1 and RANTES, called MIP/RANTES, consisting of the eight amino terminal residues of MIP-1 preceding the CC motif, and the remainder of the sequence is RANTES. The chimera is able to induce chemotaxis of human monocytes. MIP/RANTES has >100-fold reduction in binding to CCR1 and does not bind to CCR3 but retains full, functional binding to CCR5. It has equivalent affinity for CCR5 to MIP-1 and RANTES, binding with an IC₅₀ of 1.12 nM, and is able to mobilize calcium and induce endocytosis of CCR5 in PBMC in a manner equi-potent to RANTES. It also retains the ability to inhibit R5 using HIV-1 strains. Therefore, we conclude that the amino terminus of RANTES is not involved in CCR5 binding, but it is essential for CCR1 and CCR3.

Key Words: chemokine • ligand • monocyte

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