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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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    2. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
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    7. Manbir Sandhu & Aaron Cho & Ning Ma & Elizaveta Mukhaleva & Yoon Namkung & Sangbae Lee & Soumadwip Ghosh & John H. Lee & David E. Gloriam & Stéphane A. Laporte & M. Madan Babu & Nagarajan Vaidehi, 2022. "Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. 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.
    9. Jinkang Shen & Dongqi Zhang & Yao Fu & Anqi Chen & Xiaoli Yang & Haitao Zhang, 2022. "Cryo-EM structures of human bradykinin receptor-Gq proteins complexes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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