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Cell Res. 2011 Feb;21(2):305-15. doi: 10.1038/cr.2010.131. Epub 2010 Sep 14.

Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits.

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National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.


The Ca(2+) release-activated Ca(2+) (CRAC) channel pore is formed by Orai1 and gated by STIM1 after intracellular Ca(2+) store depletion. To resolve how many STIM1 molecules are required to open a CRAC channel, we fused different numbers of Orai1 subunits with functional two-tandem cytoplasmic domains of STIM1 (residues 336-485, designated as S domain). Whole-cell patch clamp recordings of these chimeric molecules revealed that CRAC current reached maximum at a stoichiometry of four Orai1 and eight S domains. Further experiments indicate that two-tandem S domains specifically interact with the C-terminus of one Orai1 subunit, and CRAC current can be gradually increased as more Orai1 subunits can interact with S domains or STIM1 proteins. Our data suggest that maximal opening of one CRAC channel requires eight STIM1 molecules, and support a model that the CRAC channel activation is not in an "all-or-none" fashion but undergoes a graded process via binding of different numbers of STIM1.

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