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

Author

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  • Xizhuo Wang

    (Temple University School of Medicine)

  • Youjun Wang

    (Temple University School of Medicine
    Beijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University)

  • Yandong Zhou

    (Temple University School of Medicine)

  • Eunan Hendron

    (Temple University School of Medicine)

  • Salvatore Mancarella

    (Temple University School of Medicine
    Present address: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA)

  • Mark D Andrake

    (Institute for Cancer Research, Fox Chase Cancer Center)

  • Brad S Rothberg

    (Temple University School of Medicine)

  • Jonathan Soboloff

    (Temple University School of Medicine)

  • Donald L Gill

    (Temple University School of Medicine)

Abstract

STIM1 and STIM2 are widely expressed endoplasmic reticulum (ER) Ca2+ sensor proteins able to translocate within the ER membrane to physically couple with and gate plasma membrane Orai Ca2+ 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.

Suggested Citation

  • Xizhuo Wang & Youjun Wang & Yandong Zhou & Eunan Hendron & Salvatore Mancarella & Mark D Andrake & Brad S Rothberg & Jonathan Soboloff & Donald L Gill, 2014. "Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site," Nature Communications, Nature, vol. 5(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4183
    DOI: 10.1038/ncomms4183
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