Conserved and species-specific STIM autoinhibition revealed by AlphaFold3-guided dissection

Authors

Liu, P., Wu, X., Huang, M., Wang, H., Hou, P., He, H., tong, l., Zhang, Y., Wang, Y.

Abstract

Store-operated Calcium (Ca2+) entry (SOCE), mediated by dynamic STIM-Orai coupling, is crucial for cellular signaling, yet the molecular architecture of STIM autoinhibition remains poorly defined. Using an AlphaFold3-guided functional validation strategy combining FRET-based biosensors, mutagenesis, and Ca2+ imaging, we systematically dissected the CC1-SOAR autoinhibitory interface in both human STIM1 and C. elegans STIM (cSTIM). Our results reveal a conserved hydrophobic core essential for maintaining the resting state in both species. Interestingly, cSTIM possesses an extended polar interaction network that strengthens autoinhibition and correlates with slower activation kinetics. Species-specific polar networks differentially modulate interface stability, providing an additional layer of regulatory tuning. This integrated approach not only validates AlphaFold3 as a powerful tool for studying dynamic regulatory interfaces but also establishes a structural framework for understanding STIM activation and disease-associated mutations, offering mechanistic insights with therapeutic implications for SOCE-related disorders.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Jul 2026.

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