Article

Electron cryo-microscopy structure of a human TRPM4 channel

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Abstract

Ca2+-activated, non-selective (CAN) ion channels sense increases of the intracellular Ca2+ concentration, producing a flux of Na+ and/or K+ ions that depolarizes the cell, thus modulating cellular Ca2+ entry. CAN channels are involved in cellular responses such as neuronal bursting activity and cardiac rhythm. Here we report the electron cryo-microscopy structure of the most widespread CAN channel, human TRPM4, bound to the agonist Ca2+ and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the ‘pole’ and four helical ‘ribs’ spanning the N-terminal TRPM homology regions (MHRs), thus holding four subunits in a crown-like architecture. We observed two decavanadate-binding sites, one in the C-terminal domain and another in the intersubunit MHR interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity. Our structure provides new insights into the function and pharmacology of both the CAN and the TRPM families.

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Acknowledgements

Cryo-EM data was collected at the David Van Andel Advanced Cryo-Electron Microscopy Suite in the Van Andel Research Institute (VARI) and we are grateful to G. Zhao and X. Meng for technical support. We thank C. Xu for help with SerialEM, the HPC team at VARI for computational support and D. Nadziejka for proofreading. This work is supported by internal funding from VARI.

Author information

Author notes

    • Paige A. Winkler
    • , Yihe Huang
    •  & Weinan Sun

    These authors contributed equally to this work.

Affiliations

  1. Van Andel Institute, 333 Bostwick Avenue N.E., Grand Rapids, Michigan 49503, USA

    • Paige A. Winkler
    • , Yihe Huang
    • , Juan Du
    •  & Wei Lü
  2. Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA

    • Weinan Sun

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Contributions

W.L. designed the project. P.A.W., Y.H. and W.L. purified TRPM4 and performed cryo-EM data collection and processing. W.S. performed electrophysiological experiments. W.L. and J.D. analysed the data and wrote the manuscript. All the authors contributed in preparing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wei Lü.

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