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STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate

Author

Listed:
  • Megumi Yamashita

    (Feinberg School of Medicine, Northwestern University)

  • Priscilla S.-W. Yeung

    (Feinberg School of Medicine, Northwestern University)

  • Christopher E. Ing

    (Molecular Structure and Function, Hospital for Sick Children, University of Toronto
    University of Toronto)

  • Beth A. McNally

    (Feinberg School of Medicine, Northwestern University)

  • Régis Pomès

    (Molecular Structure and Function, Hospital for Sick Children, University of Toronto
    University of Toronto)

  • Murali Prakriya

    (Feinberg School of Medicine, Northwestern University)

Abstract

Store-operated Ca2+ release-activated Ca2+ (CRAC) channels constitute a major pathway for Ca2+ influx and mediate many essential signalling functions in animal cells, yet how they open remains elusive. Here, we investigate the gating mechanism of the human CRAC channel Orai1 by its activator, stromal interacting molecule 1 (STIM1). We find that two rings of pore-lining residues, V102 and F99, work together to form a hydrophobic gate. Mutations of these residues to polar amino acids produce channels with leaky gates that conduct ions in the resting state. STIM1-mediated channel activation occurs through rotation of the pore helix, which displaces the F99 residues away from the pore axis to increase pore hydration, allowing ions to flow through the V102-F99 hydrophobic band. Pore helix rotation by STIM1 also explains the dynamic coupling between CRAC channel gating and ion selectivity. This hydrophobic gating mechanism has implications for CRAC channel function, pharmacology and disease-causing mutations.

Suggested Citation

  • Megumi Yamashita & Priscilla S.-W. Yeung & Christopher E. Ing & Beth A. McNally & Régis Pomès & Murali Prakriya, 2017. "STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14512
    DOI: 10.1038/ncomms14512
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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.

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