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The STIM1-binding site nexus remotely controls Orai1 channel gating.
Nat Commun. 2016 12 08; 7:13725.NC

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+Show Affiliations

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University, Beijing 100875, China.Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27929067

Citation

Zhou, Yandong, et al. "The STIM1-binding Site Nexus Remotely Controls Orai1 Channel Gating." Nature Communications, vol. 7, 2016, p. 13725.
Zhou Y, Cai X, Loktionova NA, et al. The STIM1-binding site nexus remotely controls Orai1 channel gating. Nat Commun. 2016;7:13725.
Zhou, Y., Cai, X., Loktionova, N. A., Wang, X., Nwokonko, R. M., Wang, X., Wang, Y., Rothberg, B. S., Trebak, M., & Gill, D. L. (2016). The STIM1-binding site nexus remotely controls Orai1 channel gating. Nature Communications, 7, 13725. https://doi.org/10.1038/ncomms13725
Zhou Y, et al. The STIM1-binding Site Nexus Remotely Controls Orai1 Channel Gating. Nat Commun. 2016 12 8;7:13725. PubMed PMID: 27929067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The STIM1-binding site nexus remotely controls Orai1 channel gating. AU - Zhou,Yandong, AU - Cai,Xiangyu, AU - Loktionova,Natalia A, AU - Wang,Xianming, AU - Nwokonko,Robert M, AU - Wang,Xizhuo, AU - Wang,Youjun, AU - Rothberg,Brad S, AU - Trebak,Mohamed, AU - Gill,Donald L, Y1 - 2016/12/08/ PY - 2016/05/11/received PY - 2016/10/26/accepted PY - 2016/12/9/entrez PY - 2016/12/9/pubmed PY - 2018/9/18/medline SP - 13725 EP - 13725 JF - Nature communications JO - Nat Commun VL - 7 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/27929067/The_STIM1_binding_site_nexus_remotely_controls_Orai1_channel_gating_ L2 - http://dx.doi.org/10.1038/ncomms13725 DB - PRIME DP - Unbound Medicine ER -