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Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands. Int J Mol Sci 2017 Sep 03;18(9)

Date

09/05/2017

Pubmed ID

28869519

Pubmed Central ID

PMC5618543

DOI

10.3390/ijms18091894

Scopus ID

2-s2.0-85028764300   3 Citations

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.

Author List

Moussouras NA, Getschman AE, Lackner ER, Veldkamp CT, Dwinell MB, Volkman BF

Authors

Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Binding Sites
Humans
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Conformation
Protein Binding
Receptors, Interleukin-8A
Receptors, Interleukin-8B
Structure-Activity Relationship
Tyrosine
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46