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The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry.
Adv Exp Med Biol. 2017; 993:83-98.AE

Abstract

Store-operated Ca2+ entry fulfills a crucial role in controlling Ca2+ signals in almost all cells. The Ca2+-sensing stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER) undergo complex conformational changes in response to depleted ER luminal Ca2+, allowing them to unfold and become trapped in ER-plasma membrane (PM) junctions. Dimers of STIM proteins trap and gate the plasma membrane Orai Ca2+ channels within these junctions to generate discrete zones of high Ca2+ and regulate sensitive Ca2+-dependent intracellular signaling pathways. The STIM-Orai activating region (SOAR) of STIM1 becomes exposed upon store depletion and promotes trapping of Orai1 at the PM. Residue Phe-394 within SOAR forms an integral part of the high-affinity Orai1-interacting site. Our results demonstrate that only a single active site within the dimeric SOAR domain of STIM1 is required for the activation of Orai1 channel activity. This unimolecular model is strongly supported by evidence of variable STIM1:Orai1 stoichiometry reported in many studies. We hypothesize that unimolecular coupling promotes cross-linking of channels, localizing Ca2+ signals, and regulating channel activity. We have also identified a key "nexus" region in Orai1 near the C-terminal STIM1-binding site that can be mutated to constitutively activate Ca2+ entry, mimicking STIM1 activated channels. This suggests that STIM1 mediates gating of Orai1 in an allosteric manner via interaction with the Orai1 C-terminus alone. This model suggests the dual role of STIM1 in regulating both localization and gating of Orai1 channels and has important implications for the regulation of SOCE-mediated downstream signaling and the kinetics of channel activation.

Authors+Show Affiliations

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.Beijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, 100875, People's Republic of China.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. zhouyd@psu.edu.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. dongill@psu.edu.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

28900910

Citation

Nwokonko, Robert M., et al. "The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry." Advances in Experimental Medicine and Biology, vol. 993, 2017, pp. 83-98.
Nwokonko RM, Cai X, Loktionova NA, et al. The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry. Adv Exp Med Biol. 2017;993:83-98.
Nwokonko, R. M., Cai, X., Loktionova, N. A., Wang, Y., Zhou, Y., & Gill, D. L. (2017). The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry. Advances in Experimental Medicine and Biology, 993, 83-98. https://doi.org/10.1007/978-3-319-57732-6_5
Nwokonko RM, et al. The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry. Adv Exp Med Biol. 2017;993:83-98. PubMed PMID: 28900910.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry. AU - Nwokonko,Robert M, AU - Cai,Xiangyu, AU - Loktionova,Natalia A, AU - Wang,Youjun, AU - Zhou,Yandong, AU - Gill,Donald L, PY - 2017/9/14/entrez PY - 2017/9/14/pubmed PY - 2017/12/6/medline KW - Calcium KW - Calcium sensor KW - Channel gating KW - Channels KW - Orai1 KW - STIM1 SP - 83 EP - 98 JF - Advances in experimental medicine and biology JO - Adv. Exp. Med. Biol. VL - 993 N2 - Store-operated Ca2+ entry fulfills a crucial role in controlling Ca2+ signals in almost all cells. The Ca2+-sensing stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER) undergo complex conformational changes in response to depleted ER luminal Ca2+, allowing them to unfold and become trapped in ER-plasma membrane (PM) junctions. Dimers of STIM proteins trap and gate the plasma membrane Orai Ca2+ channels within these junctions to generate discrete zones of high Ca2+ and regulate sensitive Ca2+-dependent intracellular signaling pathways. The STIM-Orai activating region (SOAR) of STIM1 becomes exposed upon store depletion and promotes trapping of Orai1 at the PM. Residue Phe-394 within SOAR forms an integral part of the high-affinity Orai1-interacting site. Our results demonstrate that only a single active site within the dimeric SOAR domain of STIM1 is required for the activation of Orai1 channel activity. This unimolecular model is strongly supported by evidence of variable STIM1:Orai1 stoichiometry reported in many studies. We hypothesize that unimolecular coupling promotes cross-linking of channels, localizing Ca2+ signals, and regulating channel activity. We have also identified a key "nexus" region in Orai1 near the C-terminal STIM1-binding site that can be mutated to constitutively activate Ca2+ entry, mimicking STIM1 activated channels. This suggests that STIM1 mediates gating of Orai1 in an allosteric manner via interaction with the Orai1 C-terminus alone. This model suggests the dual role of STIM1 in regulating both localization and gating of Orai1 channels and has important implications for the regulation of SOCE-mediated downstream signaling and the kinetics of channel activation. SN - 0065-2598 UR - https://www.unboundmedicine.com/medline/citation/28900910/The_STIM_Orai_Pathway:_Conformational_Coupling_Between_STIM_and_Orai_in_the_Activation_of_Store_Operated_Ca2+_Entry_ L2 - https://dx.doi.org/10.1007/978-3-319-57732-6_5 DB - PRIME DP - Unbound Medicine ER -