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PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling

Author

Listed:
  • Hsin-Yung Yen

    (University of Oxford
    OMass Technologies)

  • Kin Kuan Hoi

    (University of Oxford)

  • Idlir Liko

    (University of Oxford
    OMass Technologies)

  • George Hedger

    (University of Oxford)

  • Michael R. Horrell

    (University of Oxford)

  • Wanling Song

    (University of Oxford)

  • Di Wu

    (University of Oxford)

  • Philipp Heine

    (Biochemisches Institut, Universität Zürich)

  • Tony Warne

    (MRC Laboratory of Molecular Biology)

  • Yang Lee

    (MRC Laboratory of Molecular Biology)

  • Byron Carpenter

    (MRC Laboratory of Molecular Biology
    Warwick Integrative Synthetic Biology Centre, School of Life Sciences, The University of Warwick)

  • Andreas Plückthun

    (Biochemisches Institut, Universität Zürich)

  • Christopher G. Tate

    (MRC Laboratory of Molecular Biology)

  • Mark S. P. Sansom

    (University of Oxford)

  • Carol V. Robinson

    (University of Oxford)

Abstract

G-protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets1. Although detailed structural information is available for GPCRs, the effects of lipids on the receptors, and on downstream coupling of GPCRs to G proteins are largely unknown. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs. We observed preferential binding of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) over related lipids and confirm that the intracellular surface of the receptors contain hotspots for PtdIns(4,5)P2 binding. Endogenous lipids were also observed bound directly to the trimeric Gαsβγ protein complex of the adenosine A2A receptor (A2AR) in the gas phase. Using engineered Gα subunits (mini-Gαs, mini-Gαi and mini-Gα12)2, we demonstrate that the complex of mini-Gαs with the β1 adrenergic receptor (β1AR) is stabilized by the binding of two PtdIns(4,5)P2 molecules. By contrast, PtdIns(4,5)P2 does not stabilize coupling between β1AR and other Gα subunits (mini-Gαi or mini-Gα12) or a high-affinity nanobody. Other endogenous lipids that bind to these receptors have no effect on coupling, highlighting the specificity of PtdIns(4,5)P2. Calculations of potential of mean force and increased GTP turnover by the activated neurotensin receptor when coupled to trimeric Gαiβγ complex in the presence of PtdIns(4,5)P2 provide further evidence for a specific effect of PtdIns(4,5)P2 on coupling. We identify key residues on cognate Gα subunits through which PtdIns(4,5)P2 forms bridging interactions with basic residues on class A GPCRs. These modulating effects of lipids on receptors suggest consequences for understanding function, G-protein selectivity and drug targeting of class A GPCRs.

Suggested Citation

  • Hsin-Yung Yen & Kin Kuan Hoi & Idlir Liko & George Hedger & Michael R. Horrell & Wanling Song & Di Wu & Philipp Heine & Tony Warne & Yang Lee & Byron Carpenter & Andreas Plückthun & Christopher G. Tat, 2018. "PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling," Nature, Nature, vol. 559(7714), pages 423-427, July.
  • Handle: RePEc:nat:nature:v:559:y:2018:i:7714:d:10.1038_s41586-018-0325-6
    DOI: 10.1038/s41586-018-0325-6
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    Cited by:

    1. Tianqi Zhang & Jixing Lyu & Bowei Yang & Sangho D. Yun & Elena Scott & Minglei Zhao & Arthur Laganowsky, 2024. "Native mass spectrometry and structural studies reveal modulation of MsbA–nucleotide interactions by lipids," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Fabian Bumbak & James B. Bower & Skylar C. Zemmer & Asuka Inoue & Miquel Pons & Juan Carlos Paniagua & Fei Yan & James Ford & Hongwei Wu & Scott A. Robson & Ross A. D. Bathgate & Daniel J. Scott & Pau, 2023. "Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Emily A. Chapman & David S. Roberts & Timothy N. Tiambeng & Jãán Andrews & Man-Di Wang & Emily A. Reasoner & Jake A. Melby & Brad H. Li & Donguk Kim & Andrew J. Alpert & Song Jin & Ying Ge, 2023. "Structure and dynamics of endogenous cardiac troponin complex in human heart tissue captured by native nanoproteomics," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Raphael Reher & Allegra T. Aron & Pavla Fajtová & Paolo Stincone & Berenike Wagner & Alicia I. Pérez-Lorente & Chenxi Liu & Ido Y. Ben Shalom & Wout Bittremieux & Mingxun Wang & Kyowon Jeong & Marie L, 2022. "Native metabolomics identifies the rivulariapeptolide family of protease inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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