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Research Article
CALCIUM SIGNALING

Sequential activation of STIM1 links Ca2+ with luminal domain unfolding

Romana Schober https://orcid.org/0000-0002-9156-6266, Daniel Bonhenry https://orcid.org/0000-0002-6069-7642, Victoria Lunz https://orcid.org/0000-0003-2272-9655, Jinhui Zhu https://orcid.org/0000-0001-6007-8190, Adela Krizova https://orcid.org/0000-0002-7529-4504, Irene Frischauf https://orcid.org/0000-0003-0661-2932, Marc Fahrner, MengQi Zhang https://orcid.org/0000-0001-9822-1319, Linda Waldherr https://orcid.org/0000-0001-9817-1358, Tony Schmidt https://orcid.org/0000-0001-8787-7363, Isabella Derler https://orcid.org/0000-0002-4768-146X, Peter B. Stathopulos, Christoph Romanin https://orcid.org/0000-0003-3756-4136, Rüdiger H. Ettrich https://orcid.org/0000-0001-8624-7706 [email protected], and Rainer Schindl https://orcid.org/0000-0003-0896-8887 [email protected]
Science Signaling • 19 Nov 2019 • Vol 12, Issue 608 • DOI: 10.1126/scisignal.aax3194
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Keeping STIM1 unSTIMulated

Upon ER Ca2+ depletion, the ER-localized Ca2+ sensor STIM1 activates the Orai family of plasma membrane–localized Ca2+ channels to replenish Ca2+ stores. Schober et al. described the conformational changes that occur during the initial steps of STIM1 activation. The authors used biochemical and electrophysiological analyses and molecular dynamics simulations to characterize constitutively active STIM1 mutants associated with tubular aggregate myopathy or cancer, as well as naturally occurring STIM1 variants. Their results indicated that although STIM1 was stabilized by the binding of a single Ca2+ ion, it could bind to multiple Ca2+ ions, a property that was disrupted by disease-associated mutations. Furthermore, these mutations caused STIM1 to adopt an unfolded conformation similar to that caused by Ca2+ depletion in wild-type STIM1.

Abstract

The stromal interaction molecule 1 (STIM1) has two important functions, Ca2+ sensing within the endoplasmic reticulum and activation of the store-operated Ca2+ channel Orai1, enabling plasma-membrane Ca2+ influx. We combined molecular dynamics (MD) simulations with live-cell recordings and determined the sequential Ca2+-dependent conformations of the luminal STIM1 domain upon activation. Furthermore, we identified the residues within the canonical and noncanonical EF-hand domains that can bind to multiple Ca2+ ions. In MD simulations, a single Ca2+ ion was sufficient to stabilize the luminal STIM1 complex. Ca2+ store depletion destabilized the two EF hands, triggering disassembly of the hydrophobic cleft that they form together with the stable SAM domain. Point mutations associated with tubular aggregate myopathy or cancer that targeted the canonical EF hand, and the hydrophobic cleft yielded constitutively clustered STIM1, which was associated with activation of Ca2+ entry through Orai1 channels. On the basis of our results, we present a model of STIM1 Ca2+ binding and refine the currently known initial steps of STIM1 activation on a molecular level.
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Supplementary Material

Summary

Fig. S1. NFAT activation by constitutively active STIM1 mutants.
Fig. S2. Constitutive CAD dissociation for the STIM1-H72R mutant.
Fig. S3. Ca2+ ion binding to the EF-SAM domain.
Fig. S4. Ca2+-binding probability and RMSD values for the STIM1 canonical EF-hand mutants.
Fig. S5. Altered protein unfolding for the STIM1-F108I mutant.
Movie S1. Multiple Ca2+-binding events to the EF-hand domains of STIM1.
Movie S2. A single bound Ca2+ ion maintains the luminal STIM1 structure.

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Science Signaling
Volume 12 | Issue 608
November 2019

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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Acknowledgments

We thank K. Groschner and I. Abfalter for scientific advice and for carefully proofreading the manuscript. Funding: We acknowledge the support by the Austrian Science Fund (FWF) through project P28701 to R. Schindl, P27263 to C.R., P32075 and P27872 to I.F., P28123 to M.F., P27641, P30567, and LIT-2018-5-SEE-111 to I.D., and BMWFW HSRSM (PromOpt2.0) to C.R.; by the Czech Research Infrastructure for Systems Biology C4SYS (LM2015055); and by a Memorandum of Agreement between the Institute of Microbiology, Czech Academy of Sciences, and the College of Biomedical Sciences, Larkin University and by the Natural Sciences and Engineering Research Council (NSERC 05239) to P.B.S. D.B. was supported by the EFRR project Interreg Austria–Czech Republic “Czech-Austrian Center for Supracellular Medical Research (CAC-SuMeR, no. ATCZ14)” and the Czech Science Foundation (19-20728Y). R. Schindl, C.R., and R.H.E. were funded in part through a European Cooperation in Science and Technology (COST) action (BM1406) and by the program Inter-COST (project LTC17069 to R.H.E.). Access to the National Grid Infrastructure Metacentrum, and provided computational resources are acknowledged. Author contributions: R. Schindl conceived ideas, directed the work, and designed the study. I.F., V.L., and T.S. designed and generated all plasmid constructs. R. Schindl performed initial analysis of tumor genomes. A.K. performed patch-clamp experiments. R. Schober performed fluorescence experiments. R. Schober and L.W. performed Ca2+ imaging experiments. D.B. and R.H.E. performed computational modeling and MD simulations, as well as analyzed theoretical data and predictions. J.Z., M.Z., and P.B.S. performed protein expression and purification and biochemical experiments. R. Schindl analyzed data with input from the other authors. R. Schindl and R. Schober wrote the manuscript with input of D.B., V.L., A.K., I.F., P.B.S., M.F., L.W., I.D., C.R., and R.H.E. All authors discussed the results and commented on the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. The plasmid vectors used in Fig. 6 and fig. S4 (B and C) are available from P.B.S. and require a material transfer agreement with University of Western Ontario.

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Romana Schober* https://orcid.org/0000-0002-9156-6266
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Daniel Bonhenry* https://orcid.org/0000-0002-6069-7642
Center for Nanobiology and Structural Biology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Nove Hrady CZ-373 33, Czech Republic.
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Victoria Lunz https://orcid.org/0000-0003-2272-9655
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Jinhui Zhu https://orcid.org/0000-0001-6007-8190
Schulich Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
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Adela Krizova https://orcid.org/0000-0002-7529-4504
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Irene Frischauf https://orcid.org/0000-0003-0661-2932
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Marc Fahrner
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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MengQi Zhang https://orcid.org/0000-0001-9822-1319
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
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Linda Waldherr https://orcid.org/0000-0001-9817-1358
Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria.
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Tony Schmidt https://orcid.org/0000-0001-8787-7363
Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria.
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Isabella Derler https://orcid.org/0000-0002-4768-146X
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Peter B. Stathopulos
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
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Christoph Romanin https://orcid.org/0000-0003-3756-4136
Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria.
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Rüdiger H. Ettrich† https://orcid.org/0000-0001-8624-7706 [email protected]
Center for Nanobiology and Structural Biology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Nove Hrady CZ-373 33, Czech Republic.
College of Biomedical Sciences, Larkin University, Miami, FL 33169, USA.
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Rainer Schindl† https://orcid.org/0000-0003-0896-8887 [email protected]
Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria.
BioTechMed-Graz, A-8010 Graz, Austria.
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Funding Information

Interreg: EFRR project Interreg Austria - Czech Republic
Czech Science Foundation: C4SYS [LM2015055]
Austrian Science Fund: P27641 and P30567
JKU: LIT-2018-5-SEE-111
COST associaton: BM1406
Austrian Science Fund: P32075 and P27872

Notes

*
These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (R.S.); [email protected] (R.H.E.)

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Cited by
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    • Romana Schober,
    • Carmen Höglinger,
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