Pocket delipidation induced by membrane tension or modification leads to a structurally analogous mechanosensitive channel state

Summary

The mechanosensitive ion channel of large conductance MscL gates in response to membrane tension changes. Lipid removal from transmembrane pockets leads to a concerted structural and functional MscL response, but it remains unknown whether there is a correlation between the tension-mediated state and the state derived by pocket delipidation in the absence of tension. Here, we combined pulsed electron paramagnetic resonance spectroscopy and hydrogen-deuterium exchange mass spectrometry, coupled with molecular dynamics simulations under membrane tension, to investigate the structural changes associated with the distinctively derived states. Whether it is tension- or modification-mediated pocket delipidation, we find that MscL samples a similar expanded subconducting state. This is the final step of the delipidation pathway, but only an intermediate stop on the tension-mediated path, with additional tension triggering further channel opening. Our findings hint at synergistic modes of regulation by lipid molecules in membrane tension-activated mechanosensitive channels.

Graphical abstract

Highlights

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  Pocket delipidation of TM pockets stabilizes an expanded MscL state

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  HDX and EPR probe conformational transitions of MscL

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  Bilayer stretching MD independently generates a tension-activated state

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  Structural analogy between these states has implications in MS channel regulation

Abstract

Wang et al. demonstrate that delipidation of the MscL channel pockets by either membrane tension or modification stabilizes a structurally analogous expanded state. This is a crucial state in the mechanical activation pathway, hinting at direct links between tension-mediated and molecular activation in mechanosensitive ion channels.