title: Structural basis of Vta1 function in the multivesicular body sorting pathway.
abstract: The MVB pathway plays essential roles in several eukaryotic cellular processes. Proper function of the MVB pathway requires reversible membrane association of the ESCRTs, a process catalyzed by Vps4 ATPase. Vta1 regulates the Vps4 activity, but its mechanism of action was poorly understood. We report the high-resolution crystal structures of the Did2- and Vps60-binding N-terminal domain and the Vps4-binding C-terminal domain of S. cerevisiae Vta1. The C-terminal domain also mediates Vta1 dimerization and both subunits are required for its function as a Vps4 regulator. Emerging from our analysis is a mechanism of regulation by Vta1 in which the C-terminal domain stabilizes the ATP-dependent double ring assembly of Vps4. In addition, the MIT motif-containing N-terminal domain, projected by a long disordered linker, allows contact between the Vps4 disassembly machinery and the accessory ESCRT-III proteins. This provides an additional level of regulation and coordination for ESCRT-III assembly and disassembly.
authors.affiliation: Life Sciences Institute and Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Junyu
authors.initials: J
authors.lastname: Xiao
authors.forename: Hengchuan
authors.initials: H
authors.lastname: Xia
authors.forename: Jiahai
authors.initials: J
authors.lastname: Zhou
authors.forename: Ishara F
authors.initials: IF
authors.lastname: Azmi
authors.forename: Brian A
authors.initials: BA
authors.lastname: Davies
authors.forename: David J
authors.initials: DJ
authors.lastname: Katzmann
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D013045:Species Specificity; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D010446:Peptide Fragments; D029701:Saccharomyces cerevisiae Proteins; C487285:VTA1 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D000255:Adenosine Triphosphate