Short talk:
Structure of the lysosomal membrane fusion machinery

Dmitry Shvarev1, Jannis Schoppe2, Caroline König2, Angela Perz2, Nadia Füllbrunn2, Stephan Kiontke3, Lars Langemeyer2, Dovile Januliene1, Kilian Schnelle1, Daniel Kümmel4, Florian Fröhlich5, Arne Moeller1,6, Christian Ungermann2,6

1Osnabrück University, Department of Biology/Chemistry, Structural Biology section, Osnabrück, Germany,
2Osnabrück University, Department of Biology/Chemistry, Biochemistry section, Osnabrück, Germany,
3University of Marburg, Department of Plant Physiology and Photo Biology, Marburg, Germany,
4University of Münster, Department of Chemistry and Pharmacy, Institute of Biochemistry, Münster, Germany,
5Osnabrück University, Department of Biology/Chemistry, Molecular Membrane Biology group, Osnabrück, Germany,
6Osnabrück University, Center of Cellular Nanoanalytics Osnabrück (CellNanOs), Osnabrück, Germany

Lysosomes are essential for cellular recycling, nutrient signaling, autophagy and the invasion of pathogenic bacteria and viruses. 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 fulfils its function remained speculative. Here, we used cryo-electron microscopy to reveal the structure of HOPS. Unlike previously reported, HOPS is surprisingly rigid and extensive flexibility is confined to its extremities, where GTPase binding occurs. The SNARE- binding module is rigidly attached to the core, therefore, ideally positioned between the membranes to catalyze fusion. Our results explain HOPS dual functionality and unravel why tethering complexes are an essential part of the membrane fusion machinery.

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