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

Abstract
Data availability
Article and author information
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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

1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast
EMD-14964.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14964
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, consensus map covering the upper part of the complex
EMD-14965.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14965
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, consensus map covering the bottom part of the complex
EMD-14966.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14966
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, local refinement map of the SNARE-binding module
EMD-14967.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14967
1. Kümmel D
2. Kiontke S
(2022) C.t. Vps39
PDB, 7ZTY.

https://www.rcsb.org/structure/7ZTY
1. Kümmel D
2. Kiontke S
(2022) C.t. Vps39
PDB, 7ZU0.

https://www.rcsb.org/structure/7ZU0
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, local refinement map of the backbone part of the complex
EMD-14968.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14968
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, local refinement map of the bottom part of the complex (Vps18)
EMD-14969.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14969
1. Shvarev D
2. Möller A
(2022) HOPS tethering complex from yeast, local refinement map of the bottom part of the complex (Vps39)
EMD-14970.

https://deposit-pdbe.wwpdb.org/deposition/EMD-14970

Article and author information

Author details

Dmitry Shvarev

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9776-268X
Jannis Schoppe

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.
Caroline König

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.
Angela Perz

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.
Nadia Füllbrunn

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.
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.

"This ORCID iD identifies the author of this article:" 0000-0001-5822-913X
Lars Langemeyer

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4309-0910
Dovile Januliene

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3279-7590
Kilian Schnelle

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8808-594X
Daniel Kümmel

Department of Chemistry and Pharmacy, University of Münster, Münster, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3950-5914
Florian Fröhlich

Department of Biology/Chemistry, Osnabrück University, Osnabrück, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8307-2189
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.
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.

"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.

Copyright

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.