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

Peter B. Stathopulos, Rainer Schindl, Marc Fahrner, Le Zheng, Geneviève M. Gasmi-Seabrook, Martin Muik, Christoph Romanin () and Mitsuhiko Ikura ()
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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

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3963

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