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 journalArticle

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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

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Leucine
Endoplasmic Reticulum
Chemical activation
endoplasmic reticulum
leucine
Cell membranes
Phenylalanine
Histidine
Tuning
Cell Membrane
activation
membranes
Membranes
phenylalanine
histidine
Sensors
depletion
Proteins
tuning
proteins

All Science Journal Classification (ASJC) codes

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

Cite this

Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. / Wang, Xizhuo; Wang, Youjun; Zhou, Yandong; Hendron, Eunan; Mancarella, Salvatore; Andrake, Mark D.; Rothberg, Brad S.; Soboloff, Jonathan; Gill, Donald L.

In: Nature Communications, Vol. 5, 3183, 04.02.2014.

Research output: Contribution to journalArticle

Wang, X, Wang, Y, Zhou, Y, Hendron, E, Mancarella, S, Andrake, MD, Rothberg, BS, Soboloff, J & Gill, DL 2014, 'Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site', Nature Communications, vol. 5, 3183. https://doi.org/10.1038/ncomms4183
Wang, Xizhuo ; Wang, Youjun ; Zhou, Yandong ; Hendron, Eunan ; Mancarella, Salvatore ; Andrake, Mark D. ; Rothberg, Brad S. ; Soboloff, Jonathan ; Gill, Donald L. / Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. In: Nature Communications. 2014 ; Vol. 5.
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