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

144 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
Article number3183
Pages (from-to)3183
JournalNature Communications
Volume5
DOIs
StatePublished - Feb 4 2014

Keywords

  • Amino Acid Sequence
  • Binding Sites
  • Calcium Channels/metabolism
  • Cell Adhesion Molecules/chemistry
  • Humans
  • Membrane Proteins/chemistry
  • Molecular Sequence Data
  • Neoplasm Proteins/chemistry
  • ORAI1 Protein
  • Sequence Homology, Amino Acid
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2

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