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Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle

Author

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  • Yong-Seok Kim

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Jun-Hee Yeon

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Woori Ko

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Byung-Chang Suh

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

Abstract

G protein-coupled receptors (GPCRs) regulate diverse intracellular signaling pathways through the activation of heterotrimeric G proteins. However, the effects of the sequential activation–deactivation cycle of G protein on the conformational changes of GPCRs remains unknown. By developing a Förster resonance energy transfer (FRET) tool for human M3 muscarinic receptor (hM3R), we find that a single-receptor FRET probe can display the consecutive structural conversion of a receptor by G protein cycle. Our results reveal that the G protein activation evokes a two-step change in the hM3R structure, including the fast step mediated by Gq protein binding and the subsequent slower step mediated by the physical separation of the Gαq and Gβγ subunits. We also find that the separated Gαq-GTP forms a stable complex with the ligand-activated hM3R and phospholipase Cβ. In sum, the present study uncovers the real-time conformational dynamics of innate hM3R during the downstream Gq protein cycle.

Suggested Citation

  • Yong-Seok Kim & Jun-Hee Yeon & Woori Ko & Byung-Chang Suh, 2023. "Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36911-4
    DOI: 10.1038/s41467-023-36911-4
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    1. Catherine D. Van Raamsdonk & Vladimir Bezrookove & Gary Green & Jürgen Bauer & Lona Gaugler & Joan M. O’Brien & Elizabeth M. Simpson & Gregory S. Barsh & Boris C. Bastian, 2009. "Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi," Nature, Nature, vol. 457(7229), pages 599-602, January.
    2. A. J. Venkatakrishnan & Xavier Deupi & Guillaume Lebon & Franziska M. Heydenreich & Tilman Flock & Tamara Miljus & Santhanam Balaji & Michel Bouvier & Dmitry B. Veprintsev & Christopher G. Tate & Gebh, 2016. "Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region," Nature, Nature, vol. 536(7617), pages 484-487, August.
    3. Andrew C. Kruse & Jianxin Hu & Albert C. Pan & Daniel H. Arlow & Daniel M. Rosenbaum & Erica Rosemond & Hillary F. Green & Tong Liu & Pil Seok Chae & Ron O. Dror & David E. Shaw & William I. Weis & Jü, 2012. "Structure and dynamics of the M3 muscarinic acetylcholine receptor," Nature, Nature, vol. 482(7386), pages 552-556, February.
    4. Yi-Lynn Liang & Maryam Khoshouei & Alisa Glukhova & Sebastian G. B. Furness & Peishen Zhao & Lachlan Clydesdale & Cassandra Koole & Tin T. Truong & David M. Thal & Saifei Lei & Mazdak Radjainia & Rado, 2018. "Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex," Nature, Nature, vol. 555(7694), pages 121-125, March.
    5. Tao Che & Justin English & Brian E. Krumm & Kuglae Kim & Els Pardon & Reid H. J. Olsen & Sheng Wang & Shicheng Zhang & Jeffrey F. Diberto & Noah Sciaky & F. Ivy Carroll & Jan Steyaert & Daniel Wacker , 2020. "Nanobody-enabled monitoring of kappa opioid receptor states," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    6. Yi-Lynn Liang & Maryam Khoshouei & Mazdak Radjainia & Yan Zhang & Alisa Glukhova & Jeffrey Tarrasch & David M. Thal & Sebastian G. B. Furness & George Christopoulos & Thomas Coudrat & Radostin Danev &, 2017. "Phase-plate cryo-EM structure of a class B GPCR–G-protein complex," Nature, Nature, vol. 546(7656), pages 118-123, June.
    7. Titiwat Sungkaworn & Marie-Lise Jobin & Krzysztof Burnecki & Aleksander Weron & Martin J. Lohse & Davide Calebiro, 2017. "Single-molecule imaging reveals receptor–G protein interactions at cell surface hot spots," Nature, Nature, vol. 550(7677), pages 543-547, October.
    8. Yan Zhang & Bingfa Sun & Dan Feng & Hongli Hu & Matthew Chu & Qianhui Qu & Jeffrey T. Tarrasch & Shane Li & Tong Sun Kobilka & Brian K. Kobilka & Georgios Skiniotis, 2017. "Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein," Nature, Nature, vol. 546(7657), pages 248-253, June.
    Full references (including those not matched with items on IDEAS)

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