Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery

  1. Dmitry Shvarev
  2. Jannis Schoppe
  3. Caroline König
  4. Angela Perz
  5. Nadia Füllbrunn
  6. Stephan Kiontke
  7. Lars Langemeyer
  8. Dovile Januliene
  9. Kilian Schnelle
  10. Daniel Kümmel
  11. Florian Fröhlich
  12. Arne Moeller  Is a corresponding author
  13. Christian Ungermann  Is a corresponding author
  1. Osnabrück University, Germany
  2. Philipp University of Marburg, Germany
  3. University of Münster, Germany

Abstract

Lysosomes are essential for cellular recycling, nutrient signaling, autophagy, and pathogenic bacteria and viruses invasion. Lysosomal fusion is fundamental to cell survival and requires HOPS, a conserved heterohexameric tethering complex. On the membranes to be fused, HOPS binds small membrane-associated GTPases and assembles SNAREs for fusion, but how the complex fulfills its function remained speculative. Here, we used cryo-electron microscopy to reveal the structure of HOPS. Unlike previously reported, significant flexibility of HOPS is confined to its extremities, where GTPase binding occurs. The SNARE-binding module is firmly attached to the core, therefore, ideally positioned between the membranes to catalyze fusion. Our data suggest a model for how HOPS fulfills its dual functionality of tethering and fusion and indicate why it is an essential part of the membrane fusion machinery.

Data availability

All diffraction data are deposited in the PDB as indicated in the manuscript. PDB files are mentioned there.

The following data sets were generated

Article and author information

Author details

  1. Dmitry Shvarev

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9776-268X
  2. Jannis Schoppe

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Caroline König

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Angela Perz

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Nadia Füllbrunn

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephan Kiontke

    Department of Plant Physiology and Photo Biology, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5822-913X
  7. Lars Langemeyer

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4309-0910
  8. Dovile Januliene

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3279-7590
  9. Kilian Schnelle

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8808-594X
  10. Daniel Kümmel

    Department of Chemistry and Pharmacy, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3950-5914
  11. Florian Fröhlich

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8307-2189
  12. Arne Moeller

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    For correspondence
    arne.moeller@uni-osnabrueck.de
    Competing interests
    The authors declare that no competing interests exist.
  13. Christian Ungermann

    Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany
    For correspondence
    cu@uos.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4331-8695

Funding

Deutsche Forschungsgemeinschaft (SFB 944,P11)

  • Christian Ungermann

Deutsche Forschungsgemeinschaft (SFB 944,P27)

  • Arne Moeller

Deutsche Forschungsgemeinschaft (SFB 944,P20)

  • Florian Fröhlich

Deutsche Forschungsgemeinschaft (UN111/5-6)

  • Arne Moeller
  • Christian Ungermann

Deutsche Forschungsgemeinschaft (INST190/196-1 FUGG)

  • Arne Moeller

Bundesministerium fur Bildung und Forschung (BMBF/DLR 01ED2010)

  • Arne Moeller

Deutsche Forschungsgemeinschaft (SFB 944,P16)

  • Daniel Kümmel

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

Reviewing Editor

  1. Benjamin S Glick, The University of Chicago, United States

Publication history

  1. Received: June 8, 2022
  2. Accepted: September 12, 2022
  3. Accepted Manuscript published: September 13, 2022 (version 1)

Copyright

© 2022, Shvarev 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. Dmitry Shvarev
  2. Jannis Schoppe
  3. Caroline König
  4. Angela Perz
  5. Nadia Füllbrunn
  6. Stephan Kiontke
  7. Lars Langemeyer
  8. Dovile Januliene
  9. Kilian Schnelle
  10. Daniel Kümmel
  11. Florian Fröhlich
  12. Arne Moeller
  13. Christian Ungermann
(2022)
Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery
eLife 11:e80901.
https://doi.org/10.7554/eLife.80901

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