Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site

Xizhuo Wang, Youjun Wang, Yandong Zhou, Eunan Hendron, Salvatore Mancarella, Mark D. Andrake, Brad S. Rothberg, Jonathan Soboloff, Donald L. Gill

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

STIM1 and STIM2 are widely expressed endoplasmic reticulum (ER) Ca 2+ sensor proteins able to translocate within the ER membrane to physically couple with and gate plasma membrane Orai Ca 2+ channels. Although they are structurally similar, we reveal critical differences in the function of the short STIM-Orai-activating regions (SOAR) of STIM1 and STIM2. We narrow these differences in Orai1 gating to a strategically exposed phenylalanine residue (Phe-394) in SOAR1, which in SOAR2 is substituted by a leucine residue. Remarkably, in full-length STIM1, replacement of Phe-394 with the dimensionally similar but polar histidine head group prevents both Orai1 binding and gating, creating an Orai1 non-agonist. Thus, this residue is critical in tuning the efficacy of Orai activation. While STIM1 is a full Orai1-agonist, leucine-replacement of this crucial residue in STIM2 endows it with partial agonist properties, which may be critical for limiting Orai1 activation stemming from its enhanced sensitivity to store-depletion.

Original languageEnglish (US)
Article number3183
JournalNature communications
Volume5
DOIs
StatePublished - Feb 4 2014

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site'. Together they form a unique fingerprint.

Cite this