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Swing-out opening of stromal interaction molecule 1
Ferdinand Horvath1, Sascha Berlansky2, Lena Maltan2
1Department for Theoretical Biophysics, Johannes Kepler University Linz, Linz, Austria.
Protein Science : a Publication of the Protein Society
|January 24, 2023
Summary
Stromal interaction molecule 1 (STIM1) maintains a resting state via intramolecular clamping. New models reveal key interaction sites and dynamics, explaining STIM1
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Stromal interaction molecule 1 (STIM1) regulates calcium influx by sensing ER calcium levels.
- STIM1 activation involves conformational changes exposing the CAD/SOAR domain, crucial for Orai channel activation.
- In resting cells, STIM1 is held in an inactive, quiescent state by intramolecular interactions.
Purpose of the Study:
- To develop a structural model of the STIM1 resting state.
- To analyze the molecular interactions stabilizing the STIM1 quiescent conformation.
- To elucidate the mechanism of CC1α1-CAD/SOAR detachment during STIM1 activation.
Main Methods:
- Molecular docking simulations to model the STIM1 resting state.
- Molecular dynamics simulations to analyze the CC1-CAD/SOAR binding interface.
- Electrophysiology and Förster resonance energy transfer (FRET) experiments on STIM1 mutants.
Main Results:
- A structural model of the STIM1 cytosolic resting state was generated.
- Novel interaction sites (M244, I409, E370) critical for STIM1 quiescence were identified.
- Experimental validation confirmed the proposed structural model and identified key residues.
Conclusions:
- The study provides an atomistic model for the STIM1 quiescent state and CC1α1-CAD/SOAR detachment.
- Identified residues and interactions are crucial for maintaining STIM1 in its inactive conformation.
- This work advances understanding of STIM1 regulation and calcium channel activation.
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