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

Autor: Hopl, Valentina, Tiffner, Adéla, Wutscher, Armin, Sallinger, Matthias, Grabmayr, Herwig, Prantl, Magdalena, Fröhlich, Maximilian, Söllner, Julia, Weiß, Sarah, Najjar, Hadil, Nazarenko, Yuliia, Harant, Selina, Kriško, Natalia, Fahrner, Marc, Humer, Christina, Höglinger, Carmen, Krobath, Heinrich, Bonhenry, Daniel, Derler, Isabella
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Zdroj: Communications Biology; 11/16/2024, Vol. 7 Issue 1, p1-16, 16p
Abstrakt: 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 pore opening. Our findings indicate that efficient dehydration of the peripheral TM-interfaces driven by the hydrophobic effect is critical for maintaining the closed state of Orai1. We conclude that a charge close to the center of TM3 or TM4 facilitates concomitant hydration and widening of peripheral TM interfaces to trigger constitutive Orai1 pore opening to a level comparable to or exceeding that of native activated Orai1. The Ca2+ ion channel Orai1 plays an important role in T-cell activation. A charged amino acid side chain close to the center of Orai1-transmembrane domain (TM)3 or -TM4 triggers robust constitutive activity due to enhanced hydration and widening of peripheral TM-interfaces. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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