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Initial activation of STIM1, the regulator of store-operated calcium entry

Nature Structural & Molecular Biology volume 20, pages 973–981 (2013)Cite this article

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Abstract

Physiological Ca2+ signaling in T lymphocytes and other cells depends on the STIM-ORAI pathway of store-operated Ca2+ entry. STIM1 and STIM2 are Ca2+ sensors in the endoplasmic reticulum (ER) membrane, with ER-luminal domains that monitor cellular Ca2+ stores and cytoplasmic domains that gate ORAI channels in the plasma membrane. The STIM ER-luminal domain dimerizes or oligomerizes upon dissociation of Ca2+, but the mechanism transmitting activation to the STIM cytoplasmic domain was previously undefined. Using Tb3+-acceptor energy transfer, we show that dimerization of STIM1 ER-luminal domains causes an extensive conformational change in mouse STIM1 cytoplasmic domains. The conformational change, triggered by apposition of the predicted coiled-coil 1 (CC1) regions, releases the ORAI-activating domains from their interaction with the CC1 regions and allows physical extension of the STIM1 cytoplasmic domain across the gap between ER and plasma membrane and communication with ORAI channels.

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Figure 1: STIM1-PIP2 interaction.
Figure 2: Distance measurements in STIM1 cytoplasmic domain.
Figure 3: Lack of detectable CC1-CC1 association.
Figure 4: Effects of forced CC1-CC1 association.
Figure 5: Intradimer CC1-CC1 association triggers extension of the STIM1 cytoplasmic domain.
Figure 6: Model for STIM1 activation in cells.

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Acknowledgements

This work was funded by US National Institutes of Health grants AI084167 and AI40127 (to A.R. and P.G.H.) and by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada (to M.I.). Y.Z. has been supported by a postdoctoral fellowship from The Leukemia & Lymphoma Society (LLS) and by an LLS Special Fellow award, P.S. by a Human Frontier Science Program cross-disciplinary fellowship and A.G. by a Cancer Research Institute–Irvington Institute Fellowship. We thank Y. Shen (Nankai University, Tianjin, China) for the plasmid pMCSG9-SOAR and S. Sligar (University of Illinois Urbana-Champaign, Urbana, Illinois, USA) for the plasmid pMSP1D1.

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  1. Yubin Zhou

    Present address: Present address: Center for Translational Cancer Research, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, USA.,

Authors and Affiliations

  1. La Jolla Institute for Allergy & Immunology, La Jolla, California, USA

    Yubin Zhou, Prasanna Srinivasan, Shiva Razavi, Sam Seymour, Paul Meraner, Aparna Gudlur, Anjana Rao & Patrick G Hogan

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Peter B Stathopulos & Mitsuhiko Ikura

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Contributions

Y.Z. and P.G.H. designed the study. Y.Z. designed engineered proteins, developed the assays and carried out the experiments with assistance from S.R. and S.S. P.S. made a detailed study of STIM1 binding to liposomes. P.M. prepared and characterized liposomes for the binding assays. A.G. contributed recombinant proteins and technical suggestions. P.B.S. and M.I. contributed the SEC-MALS characterization of recombinant CC1. Y.Z., A.R. and P.G.H. analyzed data, with input from the other authors. Y.Z. and P.G.H. wrote the manuscript.

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Correspondence to Patrick G Hogan.

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A.R. and P.G.H. are founders of CalciMedica, Inc. and are members of its scientific advisory board.

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Zhou, Y., Srinivasan, P., Razavi, S. et al. Initial activation of STIM1, the regulator of store-operated calcium entry. Nat Struct Mol Biol 20, 973–981 (2013). https://doi.org/10.1038/nsmb.2625

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