Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
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.
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Related Subject Headings
- Surface Plasmon Resonance
- Stromal Interaction Molecule 1
- Spectrometry, Fluorescence
- Red Fluorescent Protein
- Recombinant Proteins
- Protein Conformation
- Patch-Clamp Techniques
- ORAI1 Protein
- Nuclear Magnetic Resonance, Biomolecular
- Neoplasm Proteins
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Start / End Page
Related Subject Headings
- Surface Plasmon Resonance
- Stromal Interaction Molecule 1
- Spectrometry, Fluorescence
- Red Fluorescent Protein
- Recombinant Proteins
- Protein Conformation
- Patch-Clamp Techniques
- ORAI1 Protein
- Nuclear Magnetic Resonance, Biomolecular
- Neoplasm Proteins