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Distances and charges along the Orai1 nexus-TM3 interface control STIM1 binding and pore opening
Julia Söllner1, Magdalena Prantl1, Hadil Najjar1
1Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Gruberstraße 40, 4020 Linz, Austria.
Cell Reports
|February 5, 2026
Summary
STIM1 binding to Orai1 channels initiates Ca2+ influx. Widening of the nexus-TM3 interface is crucial for STIM1-mediated Orai1 channel opening and calcium signaling.
Area of Science:
- Molecular Biology
- Biophysics
- Cell Physiology
Background:
- Calcium (Ca2+) influx via CRAC channels is vital for cellular functions.
- STIM1 protein senses Ca2+ levels and activates Orai1 channels.
- The precise mechanism of signal transmission from STIM1 to Orai1 gating is not fully understood.
Purpose of the Study:
- To investigate the conformational dynamics of the nexus-TM3 interface in Orai1 channel gating.
- To elucidate the role of this interface in signal propagation from STIM1 to the Orai1 pore.
Main Methods:
- Unnatural amino acid (UAA)-based photocrosslinking.
- Chemical crosslinking techniques.
- Site-directed mutagenesis.
Main Results:
- A widening of the nexus-TM3 interface is a key step in STIM1-induced Orai1 channel opening.
- Hydrophobicity and charge distribution within this interface influence signal propagation.
- These dynamics are essential for the cascade leading to pore opening.
Conclusions:
- The conformational dynamics of the nexus-TM3 interface are critical for Orai1 channel function.
- Understanding this interface provides insights into CRAC channel gating mechanisms.
- This study highlights the importance of inter-domain communication in ion channel regulation.
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