title: The STIM1-binding site nexus remotely controls Orai1 channel gating.
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.
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Yandong
authors.identifier: 0000-0003-3503-0296
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Loktionova
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Nwokonko
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Xizhuo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors.forename: Youjun
authors.identifier: 0000-0003-0961-1716
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Brad S
authors.identifier: 0000-0003-1982-2269
authors.initials: BS
authors.lastname: Rothberg
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Donald L
authors.identifier: 0000-0003-0587-2548
authors.initials: DL
authors.lastname: Gill
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1 / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1