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Open channel structure of MscL and the gating mechanism of mechanosensitive channels

Nature volume 418, pages 942–948 (2002)Cite this article

Abstract

Mechanosensitive channels act as membrane-embedded mechano-electrical switches, opening a large water-filled pore in response to lipid bilayer deformations. This process is critical to the response of living organisms to direct physical stimulation, such as in touch, hearing and osmoregulation. Here, we have determined the structural rearrangements that underlie these events in the large prokaryotic mechanosensitive channel (MscL) using electron paramagnetic resonance spectroscopy and site-directed spin labelling. MscL was trapped in both the open and in an intermediate closed state by modulating bilayer morphology. Transition to the intermediate state is characterized by small movements in the first transmembrane helix (TM1). Subsequent transitions to the open state are accompanied by massive rearrangements in both TM1 and TM2, as shown by large increases in probe dynamics, solvent accessibility and the elimination of all intersubunit spin–spin interactions. The open state is highly dynamic, supporting a water-filled pore of at least 25 Å, lined mostly by TM1. These structures suggest a plausible molecular mechanism of gating in mechanosensitive channels.

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Figure 1: Functional and structural correlates of MscL gating.
Figure 2: Structural rearrangements underlying the transition to the PC14 intermediate state.
Figure 3: Structural rearrangements underlying the transition to the open state.
Figure 4: Changes in the pattern of TM1 intersubunit proximities upon transition to the intermediate and open states.
Figure 5: Structure of MscL transmembrane segments in the intermediate closed state (PC14).
Figure 6: Structure of MscL TM segments in the open state.
Figure 7: A structural model of gating in MscL.

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Acknowledgements

We thank R. Nakamoto and M. Wiener for thoughtful discussions, C. Ptak for reading the manuscript, and S. Mochel for encouragement. This work was supported in part by the NIH (E.P.) and the McKnight endowment fund for neuroscience (E.P.), the Australian Research Council grants (B.M.) and the Australian Academy of Science (Scientific Visit Award to B.M). Transmembrane segment coordinates in the three conformations have been deposited in the Protein Data Bank (accession codes 1KYK, 1KYL and 1KYM).

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Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, and Center for Structural Biology, University of Virginia, Charlottesville, Virginia, 22906, USA

    Eduardo Perozo, D. Marien Cortes & Pornthep Sompornpisut

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

    Anna Kloda & Boris Martinac

  3. Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Rd, Prathumwan, 10330, Bangkok, Thailand

    Pornthep Sompornpisut

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Correspondence to Eduardo Perozo.

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Perozo, E., Cortes, D., Sompornpisut, P. et al. Open channel structure of MscL and the gating mechanism of mechanosensitive channels. Nature 418, 942–948 (2002). https://doi.org/10.1038/nature00992

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