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STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry

Author

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  • Peter B. Stathopulos

    (Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto)

  • Rainer Schindl

    (Institute of Biophysics, Johannes Kepler University Linz)

  • Marc Fahrner

    (Institute of Biophysics, Johannes Kepler University Linz)

  • Le Zheng

    (Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto)

  • Geneviève M. Gasmi-Seabrook

    (Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto)

  • Martin Muik

    (Institute of Biophysics, Johannes Kepler University Linz)

  • Christoph Romanin

    (Institute of Biophysics, Johannes Kepler University Linz)

  • Mitsuhiko Ikura

    (Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto)

Abstract

Orai1 calcium channels in the plasma membrane are activated by stromal interaction molecule-1 (STIM1), an endoplasmic reticulum calcium sensor, to mediate store-operated calcium entry (SOCE). The cytosolic region of STIM1 contains a long putative coiled-coil (CC)1 segment and shorter CC2 and CC3 domains. Here we present solution nuclear magnetic resonance structures of a trypsin-resistant CC1–CC2 fragment in the apo and Orai1-bound states. Each CC1–CC2 subunit forms a U-shaped structure that homodimerizes through antiparallel interactions between equivalent α-helices. The CC2:CC2′ helix pair clamps two identical acidic Orai1 C-terminal helices at opposite ends of a hydrophobic/basic STIM–Orai association pocket. STIM1 mutants disrupting CC1:CC1′ interactions attenuate, while variants promoting CC1 stability spontaneously activate Orai1 currents. CC2 mutations cause remarkable variability in Orai1 activation because of a dual function in binding Orai1 and autoinhibiting STIM1 oligomerization via interactions with CC3. We conclude that SOCE is activated through dynamic interplay between STIM1 and Orai1 helices.

Suggested Citation

  • Peter B. Stathopulos & Rainer Schindl & Marc Fahrner & Le Zheng & Geneviève M. Gasmi-Seabrook & Martin Muik & Christoph Romanin & Mitsuhiko Ikura, 2013. "STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3963
    DOI: 10.1038/ncomms3963
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    Cited by:

    1. 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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