Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system

Parishmita Sarma, Carlo Marion C. Carino, Deeksha Seetharama, Shubhi Pandey, Hemlata Dwivedi-Agnihotri, Xue Rui, Yubo Cao, Kouki Kawakami, Poonam Kumari, Yu-Chih Chen, Kathryn E. Luker, Prem N. Yadav, Gary D. Luker, Stéphane A. Laporte, Xin Chen, Asuka Inoue and Arun K. Shukla ()
Additional contact information
Parishmita Sarma: Indian Institute of Technology
Carlo Marion C. Carino: Tohoku University
Deeksha Seetharama: Indian Institute of Technology
Shubhi Pandey: Indian Institute of Technology
Hemlata Dwivedi-Agnihotri: Indian Institute of Technology
Xue Rui: Changzhou University
Yubo Cao: McGill University
Kouki Kawakami: Tohoku University
Poonam Kumari: CSIR-Central Drug Research Institute Sector 10
Yu-Chih Chen: University of Pittsburgh
Kathryn E. Luker: University of Michigan
Prem N. Yadav: CSIR-Central Drug Research Institute Sector 10
Gary D. Luker: University of Michigan
Stéphane A. Laporte: McGill University
Xin Chen: Changzhou University
Asuka Inoue: Tohoku University
Arun K. Shukla: Indian Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Chemokine receptors constitute an important subfamily of G protein-coupled receptors (GPCRs), and they are critically involved in a broad range of immune response mechanisms. Ligand promiscuity among these receptors makes them an interesting target to explore multiple aspects of biased agonism. Here, we comprehensively characterize two chemokine receptors namely, CXCR4 and CXCR7, in terms of their transducer-coupling and downstream signaling upon their stimulation by a common chemokine agonist, CXCL12, and a small molecule agonist, VUF11207. We observe that CXCR7 lacks G-protein-coupling while maintaining robust βarr recruitment with a major contribution of GRK5/6. On the other hand, CXCR4 displays robust G-protein activation as expected but exhibits significantly reduced βarr-coupling compared to CXCR7. These two receptors induce distinct βarr conformations even when activated by the same agonist, and CXCR7, unlike CXCR4, fails to activate ERK1/2 MAP kinase. We also identify a key contribution of a single phosphorylation site in CXCR7 for βarr recruitment and endosomal localization. Our study provides molecular insights into intrinsic-bias encoded in the CXCR4-CXCR7 system with broad implications for drug discovery.

Date: 2023
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DOI: 10.1038/s41467-023-40482-9

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