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Int. J. Mol. Sci. 2017, 18(9), 1894; doi:10.3390/ijms18091894

Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands

1
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3
Department of Chemistry, University of Wisconsin-Whitewater, Whitewater, WI 53190, USA
*
Authors to whom correspondence should be addressed.
Received: 2 August 2017 / Revised: 29 August 2017 / Accepted: 1 September 2017 / Published: 3 September 2017
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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Abstract

Tyrosine sulfation, a post-translational modification found on many chemokine receptors, typically increases receptor affinity for the chemokine ligand. A previous bioinformatics analysis suggested that a sulfotyrosine (sY)-binding site on the surface of the chemokine CXCL12 may be conserved throughout the chemokine family. However, the extent to which receptor tyrosine sulfation contributes to chemokine binding has been examined in only a few instances. Computational solvent mapping correctly identified the conserved sulfotyrosine-binding sites on CXCL12 and CCL21 detected by nuclear magnetic resonance (NMR) spectroscopy, demonstrating its utility for hot spot analysis in the chemokine family. In this study, we analyzed five chemokines that bind to CXCR2, a subset of which also bind to CXCR1, to identify hot spots that could participate in receptor binding. A cleft containing the predicted sulfotyrosine-binding pocket was identified as a principal hot spot for ligand binding on the structures of CXCL1, CXCL2, CXCL7, and CXCL8, but not CXCL5. Sulfotyrosine titrations monitored via NMR spectroscopy showed specific binding to CXCL8, but not to CXCL5, which is consistent with the predictions from the computational solvent mapping. The lack of CXCL5–sulfotyrosine interaction and the presence of CXCL8–sulfotyrosine binding suggests a role for receptor post-translational modifications regulating ligand selectivity. View Full-Text
Keywords: CXCL5; CXCL8; CXCR1; CXCR2; sulfotyrosine; post-translational modification; chemokines; NMR CXCL5; CXCL8; CXCR1; CXCR2; sulfotyrosine; post-translational modification; chemokines; NMR
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Moussouras, N.A.; Getschman, A.E.; Lackner, E.R.; Veldkamp, C.T.; Dwinell, M.B.; Volkman, B.F. Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands. Int. J. Mol. Sci. 2017, 18, 1894.

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