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 and Donald L. Gill ()
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Yandong Zhou: The Pennsylvania State University College of Medicine
Xiangyu Cai: The Pennsylvania State University College of Medicine
Natalia A. Loktionova: The Pennsylvania State University College of Medicine
Xianming Wang: The Pennsylvania State University College of Medicine
Robert M. Nwokonko: The Pennsylvania State University College of Medicine
Xizhuo Wang: The Pennsylvania State University College of Medicine
Youjun Wang: Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University
Brad S. Rothberg: Temple University School of Medicine
Mohamed Trebak: The Pennsylvania State University College of Medicine
Donald L. Gill: The Pennsylvania State University College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13725

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