Water in peripheral TM-interfaces of Orai1-channels triggers pore opening.

ABSTRACT: The activation of the Ca²⁺-channel Orai1 via the physiological activator stromal interaction molecule 1 (STIM1) requires structural rearrangements within the entire channel complex involving a series of gating checkpoints. Focusing on the gating mechanism operating along the peripheral transmembrane domain (TM) 3/TM4-interface, we report here that some charged substitutions close to the center of TM3 or TM4 lead to constitutively active Orai1 variants triggering nuclear factor of activated T-cell (NFAT) translocation into the nucleus. Molecular dynamics simulations unveil that this gain-of-function correlates with enhanced hydration at peripheral TM-interfaces, leading to increased local structural flexibility of the channel periphery and global conformational changes permitting

SUBMITTER: Hopl V 

PROVIDER: S-EPMC11569263 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature