Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1

Sanchez, Julie; Lane, Robert; Canals, Meritxell; Stone, Martin J.

Abstract

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.

Citation

Sanchez, J., Lane, R., Canals, M., & Stone, M. J. (2019). Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1. International Journal of Molecular Sciences, 20(10), 1-15. https://doi.org/10.3390/ijms20102417

• Journal Article Type: Article
• Acceptance Date: May 9, 2019
• Online Publication Date: May 15, 2019
• Publication Date: May 15, 2019
• Deposit Date: May 28, 2019
• Publicly Available Date: May 28, 2019
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Electronic ISSN: 1422-0067
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 10
• Article Number: 2417
• Pages: 1-15
• DOI: https://doi.org/10.3390/ijms20102417
• Keywords: chemokine; chemokine receptor; chemokine receptor 1 (CCR1); G protein-coupled receptor (GPCR); binding; receptor activation; biased agonism
• Public URL: https://nottingham-repository.worktribe.com/output/2099806
• Publisher URL: https://www.mdpi.com/1422-0067/20/10/2417
• Contract Date: May 28, 2019