Gating and selectivity mechanisms for the lysosomal K+channel TMEM175

  1. SeCheol Oh
  2. Navid Paknejad
  3. Richard K Hite  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States

Abstract

Transmembrane protein 175 (TMEM175) is a K+-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson's Disease. TMEM175 is evolutionarily distinct from all known channels, predicting novel ion-selectivity and gating mechanisms. Here we present cryo-EM structures of human TMEM175 in open and closed conformations, enabled by resolutions up to 2.6Å. Human TMEM175 adopts a homodimeric architecture with a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, these same residues establish a constriction essential for K+ selectivity. These studies reveal the mechanisms of permeation, selectivity and gating and lay the groundwork for understanding the role of TMEM175 in lysosomal function.

Data availability

Cryo-EM maps and atomic coordinates have been deposited with the EMDB and PDB under accession codes EMDB-21603 and PDB 6WC9 for Class 1 TMEM175 in K+, codes EMDB-21604 and PDB 6WCA for Class 2 TMEM175 in K+, codes EMDB-21605 and PDB 6WCB Class 1 TMEM175 in Cs+ and codes EMDB-21606 and PDB 6WCC for Class 2 TMEM175 in Cs+ All other reagents are available from the corresponding author upon reasonable request.

The following data sets were generated

Article and author information

Author details

  1. SeCheol Oh

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1685-5922
  2. Navid Paknejad

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Richard K Hite

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    hiter@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0496-0669

Funding

Searle Scholars Program

  • Richard K Hite

Josie Robertson Investigators Program

  • Richard K Hite

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

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Version history

  1. Received: November 7, 2019
  2. Accepted: March 29, 2020
  3. Accepted Manuscript published: March 31, 2020 (version 1)
  4. Version of Record published: April 8, 2020 (version 2)

Copyright

© 2020, Oh 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. SeCheol Oh
  2. Navid Paknejad
  3. Richard K Hite
(2020)
Gating and selectivity mechanisms for the lysosomal K+channel TMEM175
eLife 9:e53430.
https://doi.org/10.7554/eLife.53430

Share this article

https://doi.org/10.7554/eLife.53430

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