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Cross-linking of Orai1 channels by STIM proteins

Yandong Zhou, Robert M. Nwokonko, Xiangyu Cai, Natalia A. Loktionova, Raz Abdulqadir, Ping Xin, Barbara A. Niemeyer, Youjun Wang, Mohamed Trebak and Donald L. Gill
PNAS April 10, 2018. 115 (15) E3398-E3407; published ahead of print March 26, 2018. https://doi.org/10.1073/pnas.1720810115
Yandong Zhou
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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  • For correspondence: zhouyd@psu.edudongill@psu.edu
Robert M. Nwokonko
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Xiangyu Cai
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Natalia A. Loktionova
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Raz Abdulqadir
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Ping Xin
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Barbara A. Niemeyer
bDepartment of Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg 66421, Germany;
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Youjun Wang
cBeijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University, 100875 Beijing, People’s Republic of China
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Mohamed Trebak
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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Donald L. Gill
aDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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  • For correspondence: zhouyd@psu.edudongill@psu.edu
  1. Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 7, 2018 (received for review November 29, 2017)

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Significance

The work presents a unique understanding of the organization and function of two ubiquitously expressed proteins, central in generating calcium signals in all cell types. These are the intracellular calcium sensing “STIM” proteins, and the highly selective cell surface “Orai” calcium channels. We reveal that STIM proteins can cross-link Orai channels, resulting in a reorganized microenvironment within the membrane junctions in which they function, with important consequences in the generation of oscillatory calcium signals. Interestingly, we show a variant STIM protein widely expressed in cells functions to prevent the STIM–Orai cross-linking and clustering of channels. This provides important modulation of calcium signal generation and can serve to protect cells from overstimulation of the calcium signaling machinery.

Abstract

The transmembrane docking of endoplasmic reticulum (ER) Ca2+-sensing STIM proteins with plasma membrane (PM) Orai Ca2+ channels is a critical but poorly understood step in Ca2+ signal generation. STIM1 protein dimers unfold to expose a discrete STIM–Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER–PM junctions. We reveal that each monomer within the SOAR dimer interacts independently with single Orai1 subunits to mediate cross-linking between Orai1 channels. Superresolution imaging and mobility measured by fluorescence recovery after photobleaching reveal that SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function. A concatenated SOAR1 heterodimer containing one monomer point mutated at its critical Orai1 binding residue (F394H), although fully activating Orai channels, is completely defective in cross-linking Orai1 channels. Importantly, the naturally occurring STIM2 variant, STIM2.1, has an eight-amino acid insert in its SOAR unit that renders it functionally identical to the F394H mutant in SOAR1. Contrary to earlier predictions, the SOAR1–SOAR2.1 heterodimer fully activates Orai1 channels but prevents cross-linking and clustering of channels. Interestingly, combined expression of full-length STIM1 with STIM2.1 in a 5:1 ratio causes suppression of sustained agonist-induced Ca2+ oscillations and protects cells from Ca2+ overload, resulting from high agonist-induced Ca2+ release. Thus, STIM2.1 exerts a powerful regulatory effect on signal generation likely through preventing Orai1 channel cross-linking. Overall, STIM-mediated cross-linking of Orai1 channels is a hitherto unrecognized functional paradigm that likely provides an organizational microenvironment within ER–PM junctions with important functional impact on Ca2+ signal generation.

  • calcium signals
  • Orai channels
  • STIM1 protein
  • STIM2.1 protein
  • calcium oscillation

Footnotes

  • ↵1Y.Z. and R.M.N. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: zhouyd{at}psu.edu or dongill{at}psu.edu.
  • Author contributions: Y.Z., M.T., and D.L.G. designed research; Y.Z., R.M.N., X.C., N.A.L., and R.A. performed research; P.X., B.A.N., Y.W., and M.T. contributed new reagents/analytic tools; Y.Z. and R.M.N. analyzed data; and Y.Z. and D.L.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1720810115/-/DCSupplemental.

Published under the PNAS license.

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Cross-linking of Orai1 channels by STIM proteins
Yandong Zhou, Robert M. Nwokonko, Xiangyu Cai, Natalia A. Loktionova, Raz Abdulqadir, Ping Xin, Barbara A. Niemeyer, Youjun Wang, Mohamed Trebak, Donald L. Gill
Proceedings of the National Academy of Sciences Apr 2018, 115 (15) E3398-E3407; DOI: 10.1073/pnas.1720810115

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Cross-linking of Orai1 channels by STIM proteins
Yandong Zhou, Robert M. Nwokonko, Xiangyu Cai, Natalia A. Loktionova, Raz Abdulqadir, Ping Xin, Barbara A. Niemeyer, Youjun Wang, Mohamed Trebak, Donald L. Gill
Proceedings of the National Academy of Sciences Apr 2018, 115 (15) E3398-E3407; DOI: 10.1073/pnas.1720810115
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