title: The STIM-Orai coupling interface and gating of the Orai1 channel.
abstract: In virtually all cells, store-operated Ca2+entry signals are vital in controlling a spectrum of functions. The signals are mediated by STIM proteins in the ER and Orai channels in the PM which undergo a dynamic coupling process within discrete ER-PM junctional regions. This coupling is initiated by depletion of ER stored Ca2+triggering STIM proteins to undergo an intricate activation process. Thereafter, STIM proteins become trapped in the ER-PM junctions where they tether and gate PM Orai Ca2+channels. STIM1 exists as a dimer, with a single STIM-Orai activating region (SOAR) buried in the resting protein that becomes exposed upon activation. An exposed region on SOAR including the Phe-394 residue forms a critical Orai1 interacting site. Using dimeric SOAR concatemers, we reveal only one of the two sites in the SOAR dimer is needed for Orai1 activation. This unimolecular interaction of SOAR with Orai1 suggests STIM1 can cross-link Orai channels with important significance for Ca2+signaling. A critical "nexus" region in Orai1 close to the STIM1-binding site can be mutated to constitutively activate the channel mimicking the gating action of STIM1. This indicates STIM1 remotely controls Orai1 channel gating through an allosteric switch triggered by STIM1 binding only to the exposed C-terminal tail of the Orai1 channel.
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: zhouyd@psu.edu.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 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, PA 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, PA 17033, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Loktionova
authors.affiliation: Beijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, PR China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: dongill@psu.edu.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gill
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D000071740:ORAI1 Protein / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1 / Q000378:metabolism*
chemical_list: D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: Calcium channels; Calcium signals; Orai1; STIM1; Store-operated