Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2

Huma, Zil E.; Sanchez, Julie; Lim, Herman D.; Bridgford, Jessica L.; Huang, Cheng; Parker, Bradyn J.; Pazhamalil, Jiann G.; Porebski, Benjamin T.; Pfleger, Kevin D. G.; Lane, J. Robert; Canals, Meritxell; Stone, Martin J.

Abstract

Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), the chemokines MCP-2 (CCL8) and MCP-3 (CCL7) are partial agonists of their shared receptor CCR2, a key regulator of the trafficking of monocytes and macrophages that contribute to the pathology of atherosclerosis, obesity, and type 2 diabetes. Through experiments with chimeras of MCP-1 and MCP-3, we identified the chemokine amino-terminal region as being the primary determinant of both the binding and signaling selectivity of these two chemokines at CCR2. Analysis of CCR2 mutants showed that the chemokine amino terminus interacts with the major subpocket in the transmembrane helical bundle of CCR2, which is distinct fromthe interactions of some other chemokines with the minor subpockets of their receptors. These results suggest the major subpocket as a target for the development of small-molecule inhibitors of CCR2. 2017 © The Authors.

Citation

Huma, Z. E., Sanchez, J., Lim, H. D., Bridgford, J. L., Huang, C., Parker, B. J., Pazhamalil, J. G., Porebski, B. T., Pfleger, K. D. G., Lane, J. R., Canals, M., & Stone, M. J. (2017). Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. Science Signaling, 10(480), Article eaai8529. https://doi.org/10.1126/scisignal.aai8529

• Journal Article Type: Article
• Acceptance Date: May 5, 2017
• Online Publication Date: May 23, 2017
• Publication Date: May 23, 2017
• Deposit Date: Mar 6, 2019
• Publicly Available Date: Mar 6, 2019
• Journal: Science Signaling
• Print ISSN: 1945-0877
• Electronic ISSN: 1937-9145
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 480
• Article Number: eaai8529
• DOI: https://doi.org/10.1126/scisignal.aai8529
• Keywords: chemokine receptor CCR2; monocyte chemotactic protein; protein inhibitor; CCL2 protein, human; CCL7 protein, human; CCR2 protein, human; chemokine; chemokine receptor CCR2; monocyte chemotactic protein 1; monocyte chemotactic protein 3; protein binding; a
• Public URL: https://nottingham-repository.worktribe.com/output/1311840
• Publisher URL: http://stke.sciencemag.org/content/10/480/eaai8529
• Related Public URLs: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019598451&doi=10.1126%2fscisignal.aai8529&partnerID=40&md5=a5caa3e173d4e8915900acf29ae1a939
• Additional Information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling, Vol. 10, Issue 480, on 23 May 2017, DOI: 10.1126/scisignal.aai8529 .
• Contract Date: Mar 6, 2019