Rotation of the N-terminal helix triggers Gα activation

Heterotrimeric G proteins, activated by G-protein-coupled receptors (GPCRs), are central mediators of cellular signaling. Activation requires GDP release from the Gα subunit, a step attributed largely to the C-terminal α5 helix, the primary GPCR-interacting region. Contributions from other Gα regions have remained unclear. Here we show that the N-terminal helix (αN) of Gαs promotes GDP release through a rotational conformational change. Diffracted X-ray tracking revealed that engagement with an active GPCR increases αN conformational displacement. Biochemical assays and molecular dynamics simulations showed that counterclockwise rotation of αN, viewed from the extracellular side, facilitates GDP release, whereas clockwise rotation does not. Mechanistically, this αN-mediated pathway acts synergistically with α5 conformational changes and propagates through the β-sheet network within the Ras homology domain to the P-loop and the αG helix. These findings identify an αN-driven activation pathway and extend the mechanistic framework for GPCR-triggered G protein activation. Receptor engagement rotates the N-terminal helix of the G protein alpha subunit, and this motion is relayed through the protein to release bound GDP, revealing an activation pathway that works together with the long-studied C-terminal route.

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Publication Details

Journal
Nature Chemical Biology
Published
2026-10-30
DOI
https://doi.org/10.1038/s41589-026-02359-y
Citations
1
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
2.05
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Rotation of the N-terminal helix triggers Gα activation

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Nature Chemical Biology
Receptor Mechanisms and Signaling
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Rotation of the N-terminal helix triggers Gα activation

Roger K. Sunahara, Yuji C. Sasaki, Tatsuya Ikuta, Osamu Nureki, Adnan Sljoka, Keizaburo Taninaka, Ryoji Kise, Hidetaka S. Oshima, Wataru Shihoya, Asuka Inoue, Masataka Yanagawa, Manae Tatsumi, Kazuhiro Mio, Caesar Tawfeeq, Daisuke Sasaki, Yotaro Koizumi, Hiroki Arai, Wing-In Yau
article en
1 citations

Abstract

Heterotrimeric G proteins, activated by G-protein-coupled receptors (GPCRs), are central mediators of cellular signaling. Activation requires GDP release from the Gα subunit, a step attributed largely to the C-terminal α5 helix, the primary GPCR-interacting region. Contributions from other Gα regions have remained unclear. Here we show that the N-terminal helix (αN) of Gαs promotes GDP release through a rotational conformational change. Diffracted X-ray tracking revealed that engagement with an active GPCR increases αN conformational displacement. Biochemical assays and molecular dynamics simulations showed that counterclockwise rotation of αN, viewed from the extracellular side, facilitates GDP release, whereas clockwise rotation does not. Mechanistically, this αN-mediated pathway acts synergistically with α5 conformational changes and propagates through the β-sheet network within the Ras homology domain to the P-loop and the αG helix. These findings identify an αN-driven activation pathway and extend the mechanistic framework for GPCR-triggered G protein activation. Receptor engagement rotates the N-terminal helix of the G protein alpha subunit, and this motion is relayed through the protein to release bound GDP, revealing an activation pathway that works together with the long-studied C-terminal route.

Nature Chemical Biology
University of Tsukuba (JP), University of Toronto (CA), York University (CA), Tohoku University (JP), Keio University (JP), Kyoto University (JP), University of California San Diego (US), RIKEN (JP), RIKEN Center for Advanced Intelligence Project (JP), Institute of Science Tokyo (JP), International Institute for Integrative Sleep Medicine, University of Tsukuba (JP), Institute of Integrated Research, Institute of Science Tokyo (JP), Keio University Human Biology-Microbiome-Quantum Research Center (JP), National Institute of Advanced Industrial Science and Technology (JP), The University of Tokyo (JP)
Openalex Percentile: Top 11%
Receptor Mechanisms and Signaling
2.05
DOIOpen Access PDFOpenAlex
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