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J. Biol. Chem., Vol. 279, Issue 21, 22294-22305, May 21, 2004

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Identification of the Glycosaminoglycan Binding Site of the CC Chemokine, MCP-1

IMPLICATIONS FOR STRUCTURE AND FUNCTION IN VIVO^*

Elaine K. Lau, Chad D. Paavola, Zoë Johnson¶, Jean-Philippe Gaudry¶, Elena Geretti||, Frédéric Borlat¶, Andreas J. Kungl||, Amanda E. Proudfoot¶, and Tracy M. Handel**

From the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, ^¶Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland, and the ^||Department of Protein Chemistry and Biophysics, Institute of Pharmaceutical Chemistry and Pharmaceutical Technology, University of Graz, A-8010 Graz, Austria

In a recent study, we demonstrated that glycosaminoglycan (GAG) binding and oligomerization are essential for the in vivo function of the chemokines MCP-1/CCL2, RANTES/CCL5, and MIP-1/CCL4 (1). Binding to the GAG chains of cell surface proteoglycans is thought to facilitate the formation of high localized concentrations of chemokines, which in turn provide directional signals for leukocyte migration. To understand the molecular details of the chemokine-GAG interaction, in the present study we identified the GAG binding epitopes of MCP-1/CCL2 by characterizing a panel of surface alanine mutants in a series of heparin-binding assays. Using sedimentation equilibrium and cross-linking methods, we also observed that addition of heparin octasaccharide induces tetramer formation of MCP-1/CCL2. Although MCP-1/CCL2 forms a dimer in solution, both a dimer and tetramer have been observed by x-ray crystallography, providing a glimpse of the putative heparin-bound state. When the GAG binding residues are mapped onto the surface of the tetramer, the pattern that emerges is a continuous ring of basic residues encircling the tetramer, creating a positively charged surface well suited for binding GAGs. The structure also suggests several possible functional roles for GAG-induced oligomerization beyond retention of chemokines at the site of production.

Received for publication, October 13, 2003 , and in revised form, March 16, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two additional figures.

Present address: NASA Ames Research Center, Mail Stop 239-15, Moffett Field, CA 94035.

^** Supported by National Institutes of Health Grant AI37113 and American Heart Association Grant 0150322N. To whom correspondence should be addressed: Dept. of Molecular and Cell Biology, 239 Hildebrand Hall, University of California, Berkeley, CA 94720. Tel.: 510-643-9313; Fax: 510-643-9290; E-mail: handel{at}annapurna.berkeley.edu.

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