Structural basis for ion selectivity in TMEM175 K+ channels

  1. Janine D Brunner  Is a corresponding author
  2. Roman P Jakob
  3. Tobias Schulze
  4. Yvonne Neldner
  5. Anna Moroni
  6. Gerhard Thiel
  7. Timm Maier
  8. Stephan Schenck  Is a corresponding author
  1. VIB, Belgium
  2. University of Basel, Switzerland
  3. Technische Universität Darmstadt, Germany
  4. University Hospital Zürich, Switzerland
  5. University of Milan, Italy

Abstract

The TMEM175 family constitutes recently discovered K+ channels that are important for autophagosome turnover and lysosomal pH regulation and are associated with the early onset of Parkinson Disease. TMEM175 channels lack a P-loop selectivity filter, a hallmark of all known K+ channels, raising the question how selectivity is achieved. Here, we report the X-ray structure of a closed bacterial TMEM175 channel in complex with a nanobody fusion-protein disclosing bound K+ ions. Our analysis revealed that a highly conserved layer of threonine residues in the pore conveys a basal K+ selectivity. An additional layer comprising two serines in human TMEM175 increases selectivity further and renders this channel sensitive to 4-aminopyridine and Zn2+. Our findings suggest that large hydrophobic side chains occlude the pore, forming a physical gate, and that channel opening by iris-like motions simultaneously relocates the gate and exposes the otherwise concealed selectivity filter to the pore lumen.

Data availability

Atomic coordinates have been deposited at the Protein Data Bank with thefollowing unique identifiers: 6HD8, 6HD9, 6HDA, 6HDB, 6HDC, 6SWR.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Janine D Brunner

    VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium
    For correspondence
    janine.brunner@vub.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4237-9322
  2. Roman P Jakob

    Biozentrum, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Tobias Schulze

    Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Yvonne Neldner

    Department of Trauma, University Hospital Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Moroni

    Department of Biosciences, University of Milan, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1860-406X
  6. Gerhard Thiel

    Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Timm Maier

    Biozentrum, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7459-1363
  8. Stephan Schenck

    VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium
    For correspondence
    stephan.schenck@vub.be
    Competing interests
    The authors declare that no competing interests exist.

Funding

H2020 European Research Council (Advanced Grant 495 (AdG) n. 695078 noMAGIC)

  • Anna Moroni
  • Gerhard Thiel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. László Csanády, Semmelweis University, Hungary

Version history

  1. Received: November 16, 2019
  2. Accepted: April 7, 2020
  3. Accepted Manuscript published: April 8, 2020 (version 1)
  4. Version of Record published: April 22, 2020 (version 2)
  5. Version of Record updated: April 24, 2020 (version 3)

Copyright

© 2020, Brunner et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Janine D Brunner
  2. Roman P Jakob
  3. Tobias Schulze
  4. Yvonne Neldner
  5. Anna Moroni
  6. Gerhard Thiel
  7. Timm Maier
  8. Stephan Schenck
(2020)
Structural basis for ion selectivity in TMEM175 K+ channels
eLife 9:e53683.
https://doi.org/10.7554/eLife.53683

Share this article

https://doi.org/10.7554/eLife.53683

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