Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1 -: Implications for structure and function in vivo

被引:169
作者
Lau, EK
Paavola, CD
Johnson, Z
Gaudry, JP
Geretti, E
Borlat, F
Kungl, AJ
Proudfoot, AE
Handel, TM
机构
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[2] Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
[3] Graz Univ, Inst Pharmaceut Chem & Pharmaceut Technol, Dept Prot Chem & Biophys, A-8010 Graz, Austria
关键词
D O I
10.1074/jbc.M311224200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-1beta/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.
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收藏
页码:22294 / 22305
页数:12
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