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J. Biol. Chem., Vol. 281, Issue 35, 25438-25446, September 1, 2006

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Heterodimerization of CCR2 Chemokines and Regulation by Glycosaminoglycan Binding^*

Susan E. Crown¹, Yonghao Yu^¶1, Matthew D. Sweeney, Julie A. Leary¹², and Tracy M. Handel^||13

From the Department of Molecular and Cell Biology, the ^¶Department of Chemistry, University of California, Berkeley, California 94720, Genome Center, Departments of Chemistry and Molecular Cell Biology, University of California, Davis, California 95616, and the ^||Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California 92093

Despite the wide range of sequence diversity among chemokines, their tertiary structures are remarkably similar. Furthermore, many chemokines form dimers or higher order oligomers, but all characterized oligomeric structures are based primarily on two dimerization motifs represented by CC-chemokine or CXC-chemokine dimer interfaces. These observations raise the possibility that some chemokines could form unique hetero-oligomers using the same oligomerization motifs. Such interactions could modulate the overall signaling response of the receptors, thereby providing a general mechanism for regulating chemokine function. For some chemokines, homo-oligomerization has also been shown to be coupled to glycosaminoglycan (GAG)-binding. However, the effect of GAG binding on chemokine hetero-oligomerization has not yet been demonstrated. In this report, we characterized the heterodimerization of the CCR2 ligands MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (CCL7), MCP-4 (CCL13), and eotaxin (CCL11), as well as the effects of GAG binding, using electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. Strong heterodimerization was observed between CCL2 and CCL8 at the expense of homodimer formation. Using NMR, we showed that the heterodimer is predominant in solution and forms a specific CC chemokine-like dimer. By contrast, only moderate heterodimer formation was observed between CCL2·CCL13, CCL2·CCL11 and CCL8·CCL13, and no heterodimerization was observed when any other CCR2 ligand was added to CCL7. To investigate the effect of a highly sulfated GAG on the formation of heterodimers, each chemokine pair was mixed with the heparin pentasaccharide, Arixtra, and assayed by ESI-FTICR mass spectrometry. Although no CCL8·CCL11 heterodimer was observed in the absence of GAG, abundant ions corresponding to the ternary complex, CCL8·CCL11·Arixtra, were observed upon addition of Arixtra. Heterodimerization between CCL2 and CCL11 was also enhanced in the presence of Arixtra. In summary, these results indicate that some CCR2 ligands can form stable heterodimers in preference to homodimers and that these interactions, like those of homo-oligomers, can be influenced by some GAGs.

Received for publication, February 16, 2006 , and in revised form, June 15, 2006.

^* This work was supported by National Institutes of Health (NIH) Grant GM63581 (to J. A. L.), NIH Grant RO1-AI37113-09 and University of California AIDs Grant 1D03-B-005 (to T. M. H.), and a Howard Hughes predoctoral fellowship (to S. E. C.). The mass spectrometry experiments were all performed in the Leary laboratory. 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 supplemental Table S1 and Figs. S1-S5.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Depts. of Chemistry and Molecular Cell Biology, Genome Center, University of California, Davis, CA 95616. Tel.: 530-754-4987; Fax: 530-754-9658; E-mail: jaleary{at}ucdavis.edu. ³ To whom correspondence may be addressed: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 9500 Gilman Dr., MC 0684, La Jolla, CA 92093-0684. Tel.: 858-822-6656; Fax: 858-822-6655; E-mail: thandel{at}ucsd.edu.

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