1. Structural Biology and Molecular Biophysics
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Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5

  1. Jingpeng Ge
  2. Johannes Elferich
  3. April Goehring
  4. Joy Zhao
  5. Peter Schuck
  6. Eric Gouaux  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. National Institutes of Health, United States
Research Article
  • Cited 25
  • Annotations
Cite this article as: eLife 2018;7:e38770 doi: 10.7554/eLife.38770

Abstract

Hearing and balance involve the transduction of mechanical stimuli into electrical signals by deflection of bundles of stereocilia linked together by protocadherin 15 (PCDH15) and cadherin 23 'tip links'. PCDH15 transduces tip link tension into opening of a mechano-electrical transduction (MET) ion channel. PCDH15 also interacts with LHFPL5, a candidate subunit of the MET channel. Here we illuminate the PCDH15-LHFPL5 structure, showing how the complex is composed of PCDH15 and LHFPL5 subunit pairs related by a 2-fold axis. The extracellular cadherin domains define a mobile tether coupled to a rigid, 2-fold symmetric 'collar' proximal to the membrane bilayer. LHFPL5 forms extensive interactions with the PCDH15 transmembrane helices and stabilizes the overall PCDH15-LHFPL5 assembly. Our studies illuminate the architecture of the PCDH15-LHFPL5 complex, localize mutations associated with deafness, and shed new light on how forces in the PCDH15 tether may be transduced into the stereocilia membrane.

Data availability

The crystal structure of EC11-EL has been deposited to the Protein Data Bank under accession code 6C10. The three-dimensional cryo-EM density maps of the PCDH154EC-LHFPL5 complex and the PCDH151EC-LHFPL5 complex have been deposited to the EM database under the accession codes EMD-7327 and EMD-7328, respectively, and the coordinates for the structures have been deposited to the Protein Data Bank under the accession codes 6C13 and 6C14, respectively.

The following data sets were generated
    1. Gouaux E
    2. Elferich J
    3. Ge J
    (2018) Soluble domain of a membrane protein
    Publicly available at the RCSB Protein Data Bank (accession no: PDB 6C10).
    1. Gouaux E
    2. Elferich J
    3. Ge J
    (2018) Structure of a membrane protein complex
    Publicly available at the RCSB Protein Data Bank (accession no: PDB 6C13).
    1. Gouaux E
    2. Elferich J
    3. Ge J
    (2018) Structure of a membrane protein complex
    Publicly available at the Electron Microscopy Data Bank (accession no: EMD-7327).
    1. Gouaux E
    2. Elferich J
    3. Ge J
    (2018) cryoEM structure of membrane protein complex
    Publicly available at the RCSB Protein Data Bank (accession no: PDB 6C14).
    1. Gouaux E
    2. Elferich J
    3. Ge J
    (2018) cryoEM structure of membrane protein complex
    Publicly available at the Electron Microscopy Data Bank (accession no: EMD-7328).

Article and author information

Author details

  1. Jingpeng Ge

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6164-1221
  2. Johannes Elferich

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9911-706X
  3. April Goehring

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Joy Zhao

    Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter Schuck

    Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8859-6966
  6. Eric Gouaux

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    gouauxe@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8549-2360

Funding

National Institutes of Health (NIBIB intramural research program)

  • Joy Zhao
  • Peter Schuck

Howard Hughes Medical Institute

  • Eric Gouaux

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

Reviewing Editor

  1. William I Weis, Stanford University Medical Center, United States

Publication history

  1. Received: May 30, 2018
  2. Accepted: July 31, 2018
  3. Accepted Manuscript published: August 2, 2018 (version 1)
  4. Version of Record published: August 14, 2018 (version 2)
  5. Version of Record updated: September 12, 2018 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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