Article

Structures of the calcium-activated, non-selective cation channel TRPM4

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Abstract

TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1–S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.

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Change history

  • Corrected online 07 December 2017

    In the HMTL, authors Xiao-chen Bai and Youxing Jiang were reversed in the author list.

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Acknowledgements

We thank N. Nguyen for manuscript preparation, J. M. Simard and J. Bryan for providing the TRPM4 clones. Single particle cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility. We thank D. Nicastro and Z. Chen for support in facility access and data acquisition. Negatively stained sample screening was performed at UTSW Electron Microscopy core. This work was supported in part by the Howard Hughes Medical Institute (Y.J.) and by grants from the National Institutes of Health (GM079179 to Y. J.) and the Welch Foundation (grant I-1578 to Y. J.). X.B. is supported by the Cancer Prevention and Research Initiative of Texas and Virginia Murchison Linthicum Scholar in Medical Research fund.

Author information

Author notes

    • Jiangtao Guo
    •  & Ji She

    These authors contributed equally to this work.

Affiliations

  1. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390–9040, USA

    • Jiangtao Guo
    • , Ji She
    • , Weizhong Zeng
    • , Qingfeng Chen
    •  & Youxing Jiang
  2. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390–8816, USA

    • Jiangtao Guo
    • , Ji She
    • , Weizhong Zeng
    • , Qingfeng Chen
    • , Xiao-chen Bai
    •  & Youxing Jiang
  3. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390–9040, USA

    • Weizhong Zeng
    • , Qingfeng Chen
    •  & Youxing Jiang
  4. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390–9039, USA

    • Xiao-chen Bai

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Contributions

J.G. and J.S. prepared the samples; J.G., J.S., Q.C. and X.B. performed data acquisition, image processing and structure determination; W.Z. performed electrophysiology; all authors participated in research design, data analysis, and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Xiao-chen Bai or Youxing Jiang.

Reviewer Information Nature thanks R. Penner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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