Fusion at the lysosome (or the yeast vacuole) requires the conserved hexameric HOPS tethering complex. HOPS binds to the vacuolar Rab7-like GTPase Ypt7 via its subunits Vps41 and Vps39 and supports fusion by promoting SNARE assembly. In contrast to its sister complex CORVET, the Ypt7-interacting domain of Vps41 in the HOPS complex is connected to the core by a long, extended α-solenoid domain. Here, we show that this solenoid acts as a molecular ruler to position the Ypt7-interaction part of Vps41 relative to the core of HOPS to support function. Mutant complexes with a shortened or extended α-solenoid part in Vps41 still tether membranes, but fail to efficiently support their fusion. In vivo, Vps41 mutants grow poorly, show defects in vacuolar morphology, endolysosomal sorting and autophagy. Importantly, if a length-compensating linker is inserted instead of the shortened α-solenoid, these defects are rescued. This suggests that the Rab-specific Vps41 subunit requires the exact length, but not the α-solenoid domain for functionality, implying a revised model how HOPS supports fusion.

• PMID: 40159992
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Journal Article

Authors

König C, Shvarev D, Gao J, Haar E, Susan N, Auffarth K, Langemeyer L, Moeller A, Ungermann C

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