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Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating

Nature Structural Biology volume 9, pages 696–703 (2002)Cite this article

Abstract

In mechanosensitive (MS) channels, gating is initiated by changes in intra-bilayer pressure profiles originating from bilayer deformation. Here we evaluated two physical mechanisms as triggers of MS channel gating: the energetic cost of protein–bilayer hydrophobic mismatches and the geometric consequences of bilayer intrinsic curvature. Structural changes in the Escherichia coli large MS channel (MscL) were studied under nominally zero transbilayer pressures using both patch clamp and EPR spectroscopic approaches. Changes in membrane intrinsic curvature induced by the external addition of lysophosphatidylcholine (LPC) generated massive spectroscopic changes in the narrow constriction that forms the channel 'gate', trapping the channel in the fully open state. Hydrophobic mismatch alone was unable to open the channel, but decreasing bilayer thickness lowered MscL activation energy, stabilizing a structurally distinct closed channel intermediate. We propose that the mechanism of mechanotransduction in MS channels is defined by both local and global asymmetries in the transbilayer pressure profile at the lipid–protein interface.

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Figure 1: MscL gating is triggered by transbilayer pressure gradients and transduced via intra-bilayer tension changes.
Figure 2: Hydrophobic surface matching stabilizes intermediate conformations but does not fully open MscL.
Figure 3: Hydrophobic mismatch induces conformational rearrangements of MscL gate.
Figure 4: Stabilization of open MscL with mixtures of PC–LPC.
Figure 5: Mixtures of PC–LPC induce massive conformational changes in MscL
Figure 6: Asymmetries in the intra-bilayer tension gradient are required for MscL gating.
Figure 7: A model depicting the evolution of structurally distinct conformations during MscL gating.

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Acknowledgements

We thank T. Thompsom and R. Biltonen for insightful discussions and C. Ptak for critically reading the manuscript. Support and encouragement from S. Mochel is greatly appreciated. This work was supported in part by NIH (E.P.) and the McKnight endowment fund for neuroscience (E.P.), the Australian Research Council (B.M.) and the Australian Academy of Science (Scientific Visit Award to B.M).

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Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, 22906, Virginia, USA

    Eduardo Perozo & D. Marien Cortes

  2. Department of Pharmacology, Queen Elisabeth II Medical Center, University of Western Australia, Crawley, 6009, Western Australia, Australia

    Anna Kloda & Boris Martinac

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  1. Eduardo Perozo
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Correspondence to Eduardo Perozo.

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Perozo, E., Kloda, A., Cortes, D. et al. Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating. Nat Struct Mol Biol 9, 696–703 (2002). https://doi.org/10.1038/nsb827

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