Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating
Copyright policy )Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating
The Orai1-STIM1 current undergoes slow Ca(2+)-dependent inactivation (SCDI) mediated by the binding of SARAF to STIM1. Here we report the use of SCDI by SARAF as a probe of the conformation and microdomain localization of the Orai1-STIM1 complex. We find that the interaction of STIM1 with Orai1 carboxyl terminus (C terminus) and the STIM1 K-domain are required for the interaction of SARAF with STIM1 and SCDI. STIM1-Orai1 must be in a PM/ER microdomain tethered by E-Syt1, stabilized by septin4 and enriched in PI(4,5)P2 for STIM1-SARAF interaction. Targeting STIM1 to PI(4,5)P2-rich and -poor microdomains reveals that SARAF-dependent SCDI is observed only when STIM1-Orai1 are within the PI(4,5)P2-rich microdomain. Notably, store depletion results in transient localization of STIM1-Orai1 in the PI(4,5)P2-poor microdomain, which then translocates to the PI(4,5)P2-rich domain. These findings reveal the role of PM/ER tethers in the regulation of Orai1 function and a mode of regulation by PI(4,5)P2 involving translocation between PI(4,5)P2 microdomains.
- National Institute of Health Pakistan
- Chosun University Korea (Republic of)
- University of Szeged Hungary
Phosphatidylinositol 4,5-Diphosphate, Binding Sites, ORAI1 Protein, Membrane Proteins, Biological Transport, Article, Recombinant Proteins, Neoplasm Proteins, Protein Structure, Tertiary, HEK293 Cells, Intracellular Calcium-Sensing Proteins, Gene Expression Regulation, Humans, Calcium, Calcium Channels, Calcium Signaling, Ion Channel Gating, Septins, HeLa Cells, Plasmids, Protein Binding
Phosphatidylinositol 4,5-Diphosphate, Binding Sites, ORAI1 Protein, Membrane Proteins, Biological Transport, Article, Recombinant Proteins, Neoplasm Proteins, Protein Structure, Tertiary, HEK293 Cells, Intracellular Calcium-Sensing Proteins, Gene Expression Regulation, Humans, Calcium, Calcium Channels, Calcium Signaling, Ion Channel Gating, Septins, HeLa Cells, Plasmids, Protein Binding
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