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SHR Neuro Cancer Cardio Lipid Metab Microb

Schober, R; Bonhenry, D; Lunz, V; Zhu, J; Krizova, A; Frischauf, I; Fahrner, M; Zhang, M; Waldherr, L; Schmidt, T; Derler, I; Stathopulos, PB; Romanin, C; Ettrich, RH; Schindl, R.
Sequential activation of STIM1 links Ca²⁺ with luminal domain unfolding.
Sci Signal. 2019; 12(608): Doi: 10.1126/scisignal.aax3194
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Leading authors Med Uni Graz: Schindl Rainer
Co-authors Med Uni Graz: Schmidt Tony; Waldherr Linda
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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. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Find related publications in this database (using NLM MeSH Indexing): Algorithms -; Animals -; Calcium - metabolism; Cell Line, Tumor -; Cell Membrane - metabolism; EF Hand Motifs -; Endoplasmic Reticulum - metabolism; HEK293 Cells -; Humans -; Hydrophobic and Hydrophilic Interactions -; Microscopy, Confocal -; Molecular Dynamics Simulation -; Mutation -; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; ORAI1 Protein - chemistry; ORAI1 Protein - metabolism; Protein Domains -; Protein Unfolding -; Rats -; Stromal Interaction Molecule 1 - chemistry; Stromal Interaction Molecule 1 - genetics; Stromal Interaction Molecule 1 - metabolism