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STIM1 transmembrane helix dimerization captured by AI-guided transition path sampling.

Ferdinand Horvath1, Hendrik Jung2, Herwig Grabmayr3

  • 1Institute of Theoretical Physics, Johannes Kepler University Linz, 4040 Linz, Austria.

Proceedings of the National Academy of Sciences of the United States of America
|August 26, 2025
PubMed
Summary
This summary is machine-generated.

Stromal interaction molecule 1 (STIM1) protein dimerization is key for calcium sensing. AI-guided simulations reveal three distinct STIM1 transmembrane helix dimer configurations, clarifying its mechanism.

Keywords:
STIM1TM-helix dimerizationstore-operated calcium entrytransition path sampling

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Area of Science:

  • Biophysics
  • Molecular Biology
  • Calcium Signaling

Background:

  • Stromal interaction molecule 1 (STIM1) is a crucial Ca2+ sensor located in the endoplasmic reticulum (ER) membrane.
  • ER Ca2+ depletion triggers conformational changes in STIM1, initiating calcium signaling pathways.
  • The dimerization of STIM1's transmembrane (TM) domain is a critical early step in this process.

Purpose of the Study:

  • To elucidate the atomistic mechanisms governing STIM1 transmembrane helix dimerization.
  • To identify distinct STIM1 dimer configurations and their associated transition states.
  • To validate simulation findings with experimental mutagenesis studies.

Main Methods:

  • Utilized AI-guided transition path sampling (aimmd) for extensive molecular dynamics (MD) simulations.
  • Performed all-atom MD simulations in an ER-mimicking lipid bilayer environment.
  • Integrated computational findings with in vitro fluorescence-based dimerization propensity experiments.

Main Results:

  • Identified three distinct, coexisting STIM1 TM helix dimer configurations, resolving previous experimental discrepancies.
  • The dominant dimer configuration features an X-shaped interface stabilized by the SxxxG motif.
  • Mutagenesis of the SxxxG motif altered STIM1 dimerization propensity in experimental assays.
  • Characterized the transition state ensemble, highlighting the importance of luminal interhelical contacts.

Conclusions:

  • AI-guided MD simulations provide unprecedented atomistic detail into rare molecular events like STIM1 dimerization.
  • STIM1 TM helix dimerization occurs through multiple pathways, influenced by luminal interactions.
  • These findings offer a mechanistic understanding of STIM1's role in cellular calcium homeostasis.