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The STIM1-binding site nexus remotely controls Orai1 channel gating

Author

Listed:
  • Yandong Zhou

    (The Pennsylvania State University College of Medicine)

  • Xiangyu Cai

    (The Pennsylvania State University College of Medicine)

  • Natalia A. Loktionova

    (The Pennsylvania State University College of Medicine)

  • Xianming Wang

    (The Pennsylvania State University College of Medicine)

  • Robert M. Nwokonko

    (The Pennsylvania State University College of Medicine)

  • Xizhuo Wang

    (The Pennsylvania State University College of Medicine)

  • Youjun Wang

    (Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University)

  • Brad S. Rothberg

    (Temple University School of Medicine)

  • Mohamed Trebak

    (The Pennsylvania State University College of Medicine)

  • Donald L. Gill

    (The Pennsylvania State University College of Medicine)

Abstract

The ubiquitously expressed Orai Ca2+ channels are gated through a unique process of intermembrane coupling with the Ca2+-sensing STIM proteins. Despite the significance of Orai1-mediated Ca2+ signals, how gating of Orai1 is triggered by STIM1 remains unknown. A widely held gating model invokes STIM1 binding directly to Orai1 pore-forming helix. Here we report that an Orai1 C-terminal STIM1-binding site, situated far from the N-terminal pore helix, alone provides the trigger that is necessary and sufficient for channel gating. We identify a critical ‘nexus’ within Orai1 connecting the peripheral C-terminal STIM1-binding site to the Orai1 core helices. Mutation of the nexus transforms Orai1 into a persistently open state exactly mimicking the action of STIM1. We suggest that the Orai1 nexus transduces the STIM1-binding signal through a conformational change in the inner core helices, and that STIM1 remotely gates the Orai1 channel without the necessity for direct STIM1 contact with the pore-forming helix.

Suggested Citation

  • Yandong Zhou & Xiangyu Cai & Natalia A. Loktionova & Xianming Wang & Robert M. Nwokonko & Xizhuo Wang & Youjun Wang & Brad S. Rothberg & Mohamed Trebak & Donald L. Gill, 2016. "The STIM1-binding site nexus remotely controls Orai1 channel gating," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13725
    DOI: 10.1038/ncomms13725
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    Cited by:

    1. Lena Maltan & Sarah Weiß & Hadil Najjar & Melanie Leopold & Sonja Lindinger & Carmen Höglinger & Lorenz Höbarth & Matthias Sallinger & Herwig Grabmayr & Sascha Berlansky & Denis Krivic & Valentina Hop, 2023. "Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Yandong Zhou & Michelle R. Jennette & Guolin Ma & Sarah A. Kazzaz & James H. Baraniak & Robert M. Nwokonko & Mallary L. Groff & Marcela Velasquez-Reynel & Yun Huang & Youjun Wang & Donald L. Gill, 2023. "An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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