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Universal allosteric mechanism for Gα activation by GPCRs

Author

Listed:
  • Tilman Flock

    (MRC Laboratory of Molecular Biology)

  • Charles N. J. Ravarani

    (MRC Laboratory of Molecular Biology)

  • Dawei Sun

    (Laboratory of Biomolecular Research, Paul Scherrer Institut
    ETH Zurich)

  • A. J. Venkatakrishnan

    (MRC Laboratory of Molecular Biology
    † Present address: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA)

  • Melis Kayikci

    (MRC Laboratory of Molecular Biology)

  • Christopher G. Tate

    (MRC Laboratory of Molecular Biology)

  • Dmitry B. Veprintsev

    (Laboratory of Biomolecular Research, Paul Scherrer Institut
    ETH Zurich)

  • M. Madan Babu

    (MRC Laboratory of Molecular Biology)

Abstract

G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation. Here we show that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Comparison of Gα with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR–Gα system diversified rapidly, while conserving the allosteric activation mechanism.

Suggested Citation

  • Tilman Flock & Charles N. J. Ravarani & Dawei Sun & A. J. Venkatakrishnan & Melis Kayikci & Christopher G. Tate & Dmitry B. Veprintsev & M. Madan Babu, 2015. "Universal allosteric mechanism for Gα activation by GPCRs," Nature, Nature, vol. 524(7564), pages 173-179, August.
    • Handle: RePEc:nat:nature:v:524:y:2015:i:7564:d:10.1038_nature14663
    DOI: 10.1038/nature14663
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    Cited by:

    1. Jie Yin & Yanyong Kang & Aaron P. McGrath & Karen Chapman & Megan Sjodt & Eiji Kimura & Atsutoshi Okabe & Tatsuki Koike & Yuhei Miyanohana & Yuji Shimizu & Rameshu Rallabandi & Peng Lian & Xiaochen Ba, 2022. "Molecular mechanism of the wake-promoting agent TAK-925," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Xiuqing Lv & Kaixuan Gao & Jia Nie & Xin Zhang & Shuhao Zhang & Yinhang Ren & Xiaoou Sun & Qi Li & Jingrui Huang & Lijuan Liu & Xiaowen Zhang & Weishe Zhang & Xiangyu Liu, 2023. "Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
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    7. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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