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bioRxiv · 10.1101/2022.07.01.498513

State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels

Park, Y. C.·Reddy, B.·Bavi, N.·Perozo, E.·Faraldo-Gomez, J. D.
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Abstract

The force-from-lipids hypothesis of cellular mechanosensation posits that membrane channels open and close in response to changes in the physical state of the lipid bilayer, induced for example by lateral tension. Here, we investigate the molecular basis for this transduction mechanism by studying the mechanosensitive ion channel MscS from Escherichia coli and its eukaryotic homolog, MSL1 from Arabidopsis thaliana. First, we use single-particle cryo-EM to determine the structure of a novel open conformation of wild-type MscS, stabilized in a thinned lipid nanodisc. Compared with the closed state, the structure shows a reconfiguration of helices TM1, TM2 and TM3a, and widening of the central pore. Based on these structures, we examined how the morphology of the lipid bilayer is altered upon gating, using molecular dynamics simulations. The simulations reveal that closed-state MscS causes drastic protrusions in the inner leaflet of the lipid bilayer, both in the absence and presence of lateral tension, and for different lipid compositions. These deformations arise to provide adequate solvation to hydrophobic features of the protein surface in this conformation, and clearly reflect a high energy conformation for the membrane, particularly under tension. Strikingly, these protrusions are largely eradicated upon channel opening. An analogous computational study of open and closed MSL1 recapitulates these findings. The gating equilibrium of MscS channels thus appears to be dictated by two opposing conformational preferences, namely those of the lipid membrane and of the protein structure. We propose a membrane deformation model of mechanosensation, which posits that tension shifts the gating equilibrium towards the conductive state not because it alters the mode in which channel and lipids interact but because it increases the energetic cost of the morphological perturbations in the membrane induced by to the closed state.

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Park, Y. C., Reddy, B., Bavi, N., Perozo, E., Faraldo-Gomez, J. D.. 2022-07-02. State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels. https://doi.org/10.1101/2022.07.01.498513

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