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Structure of the M2 muscarinic receptor–β-arrestin complex in a lipid nanodisc

Author

Listed:
  • Dean P. Staus

    (Duke University Medical Center
    Duke University Medical Center)

  • Hongli Hu

    (Stanford University School of Medicine
    The Chinese University of Hong Kong)

  • Michael J. Robertson

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Alissa L. W. Kleinhenz

    (Duke University Medical Center
    Duke University Medical Center
    University of Michigan)

  • Laura M. Wingler

    (Duke University Medical Center
    Duke University Medical Center)

  • William D. Capel

    (Duke University Medical Center)

  • Naomi R. Latorraca

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Robert J. Lefkowitz

    (Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins2. In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of β-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of β-arrestin 1 (βarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R–βarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of βarr1 to phosphorylated receptor residues and insertion of the finger loop of βarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R–heterotrimeric Go protein complex3. Moreover, the cryo-electron microscopy map reveals that the C-edge of βarr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of β-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.

Suggested Citation

  • Dean P. Staus & Hongli Hu & Michael J. Robertson & Alissa L. W. Kleinhenz & Laura M. Wingler & William D. Capel & Naomi R. Latorraca & Robert J. Lefkowitz & Georgios Skiniotis, 2020. "Structure of the M2 muscarinic receptor–β-arrestin complex in a lipid nanodisc," Nature, Nature, vol. 579(7798), pages 297-302, March.
  • Handle: RePEc:nat:nature:v:579:y:2020:i:7798:d:10.1038_s41586-020-1954-0
    DOI: 10.1038/s41586-020-1954-0
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    Cited by:

    1. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Pankaj Sharma & Elena Maklashina & Markus Voehler & Sona Balintova & Sarka Dvorakova & Michal Kraus & Katerina Hadrava Vanova & Zuzana Nahacka & Renata Zobalova & Stepana Boukalova & Kristyna Cunatova, 2024. "Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Raphael S. Haider & Edda S. F. Matthees & Julia Drube & Mona Reichel & Ulrike Zabel & Asuka Inoue & Andy Chevigné & Cornelius Krasel & Xavier Deupi & Carsten Hoffmann, 2022. "β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Yasmin Aydin & Thore Böttke & Jordy Homing Lam & Stefan Ernicke & Anna Fortmann & Maik Tretbar & Barbara Zarzycka & Vsevolod V. Gurevich & Vsevolod Katritch & Irene Coin, 2023. "Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Amal El Daibani & Joseph M. Paggi & Kuglae Kim & Yianni D. Laloudakis & Petr Popov & Sarah M. Bernhard & Brian E. Krumm & Reid H. J. Olsen & Jeffrey Diberto & F. Ivy Carroll & Vsevolod Katritch & Bern, 2023. "Molecular mechanism of biased signaling at the kappa opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    8. Ruibo Zhai & Zhuoqi Wang & Zhaofei Chai & Xiaogang Niu & Conggang Li & Changwen Jin & Yunfei Hu, 2023. "Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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