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A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1)

Marc Fahrner1, Martin Muik1, Rainer Schindl1

  • 1From the Life Science Center JKU, Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria.

The Journal of Biological Chemistry
|October 25, 2014
PubMed

Insights

Store-operated calcium entry, vital for immunity, is controlled by STIM1 protein interactions. New research reveals sequential coiled-coil interactions within STIM1 regulate its conformation and clustering, fine-tuning calcium channel activation.

Area of Science:

  • Cell Biology
  • Immunology
  • Biophysics

Background:

  • Store-operated calcium (Ca2+) entry is crucial for adaptive immunity.
  • This process is initiated by the endoplasmic reticulum (ER) Ca2+ sensor STIM1, which interacts with the Orai1 Ca2+ channel.
  • ER Ca2+ store depletion triggers STIM1/Orai1 interaction via conformational changes and co-clustering.

Purpose of the Study:

  • To investigate the role of coiled-coil (CC) interactions in STIM1 conformation and cluster formation.
  • To dissect the sequential activation mechanism of STIM1 cytosolic domains.
  • To understand how STIM1 auto-inhibition controls Orai1 channel activation.

Main Methods:

  • Development of a novel approach: FRET-derived Interaction in a Restricted Environment (FIRE).
  • Analysis of STIM1 auto-inhibition mechanisms.
  • Investigation of STIM1/Orai1 interactions and clustering.

Main Results:

  • Evidence for a sequential activation mechanism in STIM1 cytosolic domains.
  • Interaction between CC1 and CC3 segments regulates SOAR/CAD exposure.
  • CC3-mediated higher-order oligomerization and cluster formation are controlled by CC1-CC3 interaction.
  • Dual levels of STIM1 auto-inhibition provide efficient control over Orai1 channel activation.

Conclusions:

  • STIM1 auto-inhibition involves sequential coiled-coil interactions.
  • These interactions precisely control STIM1 conformation, oligomerization, and clustering.
  • This mechanism ensures efficient coupling and activation of Orai1 channels for store-operated calcium entry.

Keywords:
Calcium Release-activated Calcium Channel Protein 1 (ORAI1)FluorescencePatch ClampSignal TransductionStromal Interaction Molecule 1 (STIM1)

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