Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Rik van der Kant, Caspar T H Jonker, Ruud H Wijdeven, Jeroen Bakker, Lennert Janssen, Judith Klumperman, Jacques Neefjes

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Trafficking of cargo through the endosomal system depends on endosomal fusion events mediated by SNARE proteins, Rab-GTPases, and multisubunit tethering complexes. The CORVET and HOPS tethering complexes, respectively, regulate early and late endosomal tethering and have been characterized in detail in yeast where their sequential membrane targeting and assembly is well understood. Mammalian CORVET and HOPS subunits significantly differ from their yeast homologues, and novel proteins with high homology to CORVET/HOPS subunits have evolved. However, an analysis of the molecular interactions between these subunits in mammals is lacking. Here, we provide a detailed analysis of interactions within the mammalian CORVET and HOPS as well as an additional endosomal-targeting complex (VIPAS39-VPS33B) that does not exist in yeast. We show that core interactions within CORVET and HOPS are largely conserved but that the membrane-targeting module in HOPS has significantly changed to accommodate binding to mammalian-specific RAB7 interacting lysosomal protein (RILP). Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome-associated mutations in VPS33B selectively disrupt recruitment to late endosomes by RILP or binding to its partner VIPAS39. Within the shared core of CORVET/HOPS, we find that VPS11 acts as a molecular switch that binds either CORVET-specific TGFBRAP1 or HOPS-specific VPS39/RILP thereby allowing selective targeting of these tethering complexes to early or late endosomes to time fusion events in the endo/lysosomal pathway.

Original languageEnglish
Pages (from-to)30280-90
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number51
DOIs
Publication statusPublished - 18 Dec 2015
Externally publishedYes

Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Amino Acid Substitution
  • Arthrogryposis/genetics
  • Cell Line
  • Cholestasis/genetics
  • Endosomes/genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Multiprotein Complexes/genetics
  • Mutation, Missense
  • Renal Insufficiency/genetics
  • Vesicular Transport Proteins/genetics

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