Inside-out Ca(2+) signalling prompted by STIM1 conformational switch

Nat Commun. 2015 Jul 17;6:7826. doi: 10.1038/ncomms8826.


Store-operated Ca(2+) entry mediated by STIM1 and ORAI1 constitutes one of the major Ca(2+) entry routes in mammalian cells. The molecular choreography of STIM1-ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca(2+) store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca(2+) signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels / metabolism*
  • Calcium Signaling*
  • Chromatography, Liquid
  • Circular Dichroism
  • Endoplasmic Reticulum / metabolism
  • Escherichia coli
  • Green Fluorescent Proteins
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Luminescent Proteins
  • Membrane Proteins / metabolism*
  • Microscopy, Confocal
  • Models, Molecular
  • Native Polyacrylamide Gel Electrophoresis
  • Neoplasm Proteins / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • ORAI1 Protein
  • Patch-Clamp Techniques
  • Protein Conformation
  • Recombinant Proteins
  • Spectrometry, Fluorescence
  • Stromal Interaction Molecule 1
  • Surface Plasmon Resonance


  • Calcium Channels
  • Luminescent Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Recombinant Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • red fluorescent protein
  • Green Fluorescent Proteins