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Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating

Author

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  • Jozsef Maléth

    (Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH
    University of Szeged)

  • Seok Choi

    (Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH
    College of Medicine, Chosun University)

  • Shmuel Muallem

    (Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH)

  • Malini Ahuja

    (Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH)

Abstract

The Orai1–STIM1 current undergoes slow Ca2+-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.

Suggested Citation

  • Jozsef Maléth & Seok Choi & Shmuel Muallem & Malini Ahuja, 2014. "Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6843
    DOI: 10.1038/ncomms6843
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