Article | Published:

Structure of the mechanically activated ion channel Piezo1

Nature volume 554, pages 481486 (22 February 2018) | Download Citation

Abstract

Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception and vascular development. Piezo proteins are distinct from other ion channels and their structure remains poorly defined, which impedes detailed study of their gating and ion permeation properties. Here we report a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-bladed propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-transmembrane helical bundles that we term Piezo repeats. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically. The structure provides a foundation to dissect further how Piezo channels are regulated by mechanical force.

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Acknowledgements

We thank H. Turner and G. Ozorowski for assistance with electron microscopy data collection. We acknowledge early efforts to characterize Piezo1 using electron microscopy by E. Wilson-Kubalek and R. Milligan, and S. Kakuda for screening purification conditions. We thank A. Sobolevsky for critical reading of the manuscript, and members of the Ward and Patapoutian laboratories for discussion. This work was supported by a Ray Thomas Edwards Foundation grant to A.B.W. and National Institutes of Health (NIH) grants NS083174 and DE022358 to A.P. Computational analyses were performed using shared instrumentation funded by NIH 1-S10OD021634. A.P. is an investigator of the Howard Hughes Medical Institute. This is manuscript 29582 from The Scripps Research Institute.

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Affiliations

  1. Howard Hughes Medical Institute, Department of Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA

    • Kei Saotome
    • , Swetha E. Murthy
    • , Jennifer M. Kefauver
    • , Tess Whitwam
    •  & Ardem Patapoutian
  2. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Kei Saotome
    • , Jennifer M. Kefauver
    •  & Andrew B. Ward

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Contributions

K.S. prepared electron microscopy samples, collected and processed electron microscopy data, built the structural model and conducted fluorescence-detection size-exclusion chromatography analysis. S.E.M. carried out electrophysiological experiments and data analysis. J.M.K. developed sample preparation protocols. T.W. carried out immunostaining experiments. A.P. and A.B.W. supervised the project. K.S. drafted the manuscript, which was edited by A.P. and A.B.W. with input from all authors.

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ardem Patapoutian or Andrew B. Ward.

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Extended data

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  1. 1.

    Supplementary Data

    Sequence alignment of Piezo orthologues. Amino acid sequence alignment of selected regions of mouse Piezo1 (mPiezo1; UniProt E2JF22), human Piezo1 (hPiezo1; UniProt Q92508), mouse Piezo2 (mPiezo2, UniProt Q8CD54), human Piezo2 (hPiezo2, UniProt Q9H5I5), fruit fly Piezo (dmPiezo, UniProt M9MSG8). Structural features are annotated above the mPiezo1 sequence. Unmodeled regions are depicted as dotted lines.

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https://doi.org/10.1038/nature25453

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