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

Abstract text (incl. figure legends and references)

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.

Figure 1. Composition and architecture of the yeast HOPS complex. A, Composite cryo-EM map from local refinement maps. B, Atomic model of the HOPS complex. C, Schematic representation of the HOPS complex.

References:

[1] Shvarev, Schoppe, König et al. (2022) bioRxiv, doi.org/10.1101/2022.05.05.490745.