Structural basis of Vta1 function in the multivesicular body sorting pathway.
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.
Xiao
Junyu
J
Life Sciences Institute and Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
Xia
Hengchuan
H
Zhou
Jiahai
J
Azmi
Ishara F
IF
Davies
Brian A
BA
Katzmann
David J
DJ
Xu
Zhaohui
Z
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
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