The STIM1-binding site nexus remotely controls Orai1 channel gating

Yandong Zhou, Xiangyu Cai, Natalia A. Loktionova, Xianming Wang, Robert M. Nwokonko, Xizhuo Wang, Youjun Wang, Brad S. Rothberg, Mohamed Trebak, Donald L. Gill

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


The ubiquitously expressed Orai Ca2+ channels are gated through a unique process of intermembrane coupling with the Ca2+ -sensing STIM proteins. Despite the significance of Orai1-mediated Ca2+ signals, how gating of Orai1 is triggered by STIM1 remains unknown. A widely held gating model invokes STIM1 binding directly to Orai1 pore-forming helix. Here we report that an Orai1 C-terminal STIM1-binding site, situated far from the N-terminal pore helix, alone provides the trigger that is necessary and sufficient for channel gating. We identify a critical 'nexus' within Orai1 connecting the peripheral C-terminal STIM1-binding site to the Orai1 core helices. Mutation of the nexus transforms Orai1 into a persistently open state exactly mimicking the action of STIM1. We suggest that the Orai1 nexus transduces the STIM1-binding signal through a conformational change in the inner core helices, and that STIM1 remotely gates the Orai1 channel without the necessity for direct STIM1 contact with the pore-forming helix.

Original languageEnglish (US)
Article number13725
JournalNature communications
StatePublished - Dec 8 2016

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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