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

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Store-operated Ca2+ entry is a fundamental cellular process mediated by STIM1 and ORAI1.
• The precise molecular mechanisms governing STIM1-ORAI1 channel gating remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanistic underpinnings of STIM1-ORAI1 channel gating.
• To investigate the role of the STIM1 transmembrane domain (STIM1-TM) in initiating calcium signaling.

Main Methods:

• Utilized a gain-of-function mutation in the STIM1 transmembrane domain.
• Analyzed conformational changes in STIM1 using biophysical and biochemical approaches.
• Identified critical autoinhibitory residues within the STIM1 cytoplasmic domain (STIM1-CT).

Main Results:

• Local rearrangement of STIM1-TM, not altered oligomerization, induces conformational changes in the STIM1 juxtamembrane coiled-coil region.
• Identified key residues in STIM1-CT responsible for autoinhibition.
• Proposed a model where STIM1-TM reorganization extends STIM1-CT to activate ORAI1.

Conclusions:

• STIM1 transmembrane domain reorganization is a key trigger for store-operated calcium entry.
• Autoinhibition by STIM1-CT is relieved through conformational changes initiated by STIM1-TM.
• This provides a novel mechanistic model for inside-out calcium signaling via STIM1-ORAI1.