title: Structural basis of Vps33A recruitment to the human HOPS complex by Vps16.
abstract: The multisubunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for late endosome-lysosome and autophagosome-lysosome fusion in mammals. We have determined the crystal structure of the human HOPS subunit Vps33A, confirming its identity as a Sec1/Munc18 family member. We show that HOPS subunit Vps16 recruits Vps33A to the human HOPS complex and that residues 642-736 are necessary and sufficient for this interaction, and we present the crystal structure of Vps33A in complex with Vps16(642-736). Mutations at the binding interface disrupt the Vps33A-Vps16 interaction both in vitro and in cells, preventing recruitment of Vps33A to the HOPS complex. The Vps33A-Vps16 complex provides a structural framework for studying the association between Sec1/Munc18 proteins and tethering complexes.
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom. scg34@cam.ac.uk
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Graham
authors.forename: Lena
authors.initials: L
authors.lastname: Wartosch
authors.forename: Sally R
authors.initials: SR
authors.lastname: Gray
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Scourfield
authors.forename: Janet E
authors.initials: JE
authors.lastname: Deane
authors.forename: J Paul
authors.initials: JP
authors.lastname: Luzio
authors.forename: David J
authors.initials: DJ
authors.lastname: Owen
mesh_terms: D001665:Binding Sites / Q000235:genetics; D004926:Escherichia coli; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D013045:Species Specificity; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; C424439:VPS16 protein, human; C424440:VPS33A protein, human; D033921:Vesicular Transport Proteins
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