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Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor

Author

Listed:
  • Jie Heng

    (Tsinghua University
    Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Yunfei Hu

    (Peking University
    Chinese Academy of Science)

  • Guillermo Pérez-Hernández

    (Institute of Medical Physics and Biophysics)

  • Asuka Inoue

    (Tohoku University)

  • Jiawei Zhao

    (Tsinghua University
    Tsinghua University)

  • Xiuyan Ma

    (Tsinghua University)

  • Xiaoou Sun

    (Tsinghua University)

  • Kouki Kawakami

    (Tohoku University)

  • Tatsuya Ikuta

    (Tohoku University)

  • Jienv Ding

    (Peking University
    Peking University)

  • Yujie Yang

    (Peking University)

  • Lujia Zhang

    (Tsinghua University)

  • Sijia Peng

    (Tsinghua University)

  • Xiaogang Niu

    (Peking University)

  • Hongwei Li

    (Peking University)

  • Ramon Guixà-González

    (Paul Scherrer Institute)

  • Changwen Jin

    (Peking University)

  • Peter W. Hildebrand

    (Institute of Medical Physics and Biophysics
    University Leipzig
    Berlin Institute of Health)

  • Chunlai Chen

    (Tsinghua University
    Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

Abstract

Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The β2 adrenergic receptor’s (β2AR) 71 amino acid CT is a substrate for GPCR kinases and binds β-arrestins to regulate signaling. Here we show that the β2AR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking β-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged β2AR-CT serves as an autoinhibitory factor via interacting with the positively charged cytoplasmic surface of the receptor to limit access to G-proteins. The stability of this interaction is influenced by agonists and allosteric modulators, emphasizing that the CT plays important role in allosterically regulating GPCR activation.

Suggested Citation

  • Jie Heng & Yunfei Hu & Guillermo Pérez-Hernández & Asuka Inoue & Jiawei Zhao & Xiuyan Ma & Xiaoou Sun & Kouki Kawakami & Tatsuya Ikuta & Jienv Ding & Yujie Yang & Lujia Zhang & Sijia Peng & Xiaogang N, 2023. "Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37233-1
    DOI: 10.1038/s41467-023-37233-1
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    References listed on IDEAS

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    1. Yutaro Shiraishi & Mei Natsume & Yutaka Kofuku & Shunsuke Imai & Kunio Nakata & Toshimi Mizukoshi & Takumi Ueda & Hideo Iwaï & Ichio Shimada, 2018. "Phosphorylation-induced conformation of β2-adrenoceptor related to arrestin recruitment revealed by NMR," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. David M. Thal & Alisa Glukhova & Patrick M. Sexton & Arthur Christopoulos, 2018. "Structural insights into G-protein-coupled receptor allostery," Nature, Nature, vol. 559(7712), pages 45-53, July.
    3. Tilman Flock & Alexander S. Hauser & Nadia Lund & David E. Gloriam & Santhanam Balaji & M. Madan Babu, 2017. "Selectivity determinants of GPCR–G-protein binding," Nature, Nature, vol. 545(7654), pages 317-322, May.
    4. G. Glenn Gregorio & Matthieu Masureel & Daniel Hilger & Daniel S. Terry & Manuel Juette & Hong Zhao & Zhou Zhou & Jose Manuel Perez-Aguilar & Maria Hauge & Signe Mathiasen & Jonathan A. Javitch & Hare, 2017. "Single-molecule analysis of ligand efficacy in β2AR–G-protein activation," Nature, Nature, vol. 547(7661), pages 68-73, July.
    5. Aaron M. Ring & Aashish Manglik & Andrew C. Kruse & Michael D. Enos & William I. Weis & K. Christopher Garcia & Brian K. Kobilka, 2013. "Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody," Nature, Nature, vol. 502(7472), pages 575-579, October.
    6. Xiangyu Liu & Seungkirl Ahn & Alem W. Kahsai & Kai-Cheng Meng & Naomi R. Latorraca & Biswaranjan Pani & A. J. Venkatakrishnan & Ali Masoudi & William I. Weis & Ron O. Dror & Xin Chen & Robert J. Lefko, 2017. "Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure," Nature, Nature, vol. 548(7668), pages 480-484, August.
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