Tension mediated mechanical activation and pocket delipidation lead to an analogous MscL state

Abstract

The mechanosensitive channel of large conductance MscL gates in response to tension changes in the membrane to allow the exchange of molecules through its pore. Native ligands that bind and modulate MscL are unknown and trapping an activated state has been challenging. Disruption of lipid access to tension-sensitive transmembrane pockets by modification leads to a concerted structural and functional MscL response. However, it is unknown whether there is structural correlation between tension mediated and molecular activation in mechanosensitive channels. Here, we combine HDX mass spectrometry and ESEEM solvent accessibility measurements on MscL, coupled with molecular dynamics under bilayer tension, to investigate the structural changes associated with the two distinctively derived states. Membrane thinning is not sufficient to hydrate the MscL pore, when lipids are trapped in the pockets, under tensions capable to gate the native channel. Tension and molecule stabilised states present analogous MscL structures, suggesting a link between these two distinct activation mechanisms. These findings could hint at synergistic modes of regulation in mechanosensitive ion channels with implications for their multimodality.