2. Academic Validation
  3. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry

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

  • Nat Commun. 2013;4:2963. doi: 10.1038/ncomms3963.
Peter B Stathopulos 1,  Rainer Schindl 2,  Marc Fahrner 2,  Le Zheng 1,  Geneviève M Gasmi-Seabrook 1,  Martin Muik 2,  Christoph Romanin 2,  Mitsuhiko Ikura 1
Affiliations

Affiliations

  • 1 University Health Network and Department of Medical Biophysics, Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto, Room 4-804, MaRS TMDT, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
  • 2 Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria.
PMID: 24351972 DOI: 10.1038/ncomms3963
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.

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