Vps4 disassembles an ESCRT-III filament by global unfolding and processive translocation

Nat Struct Mol Biol. 2015 Jun;22(6):492-8. doi: 10.1038/nsmb.3015. Epub 2015 May 4.


The AAA+ ATPase Vps4 disassembles ESCRT-III and is essential for HIV-1 budding and other pathways. Vps4 is a paradigmatic member of a class of hexameric AAA+ ATPases that disassemble protein complexes without degradation. To distinguish between local displacement versus global unfolding mechanisms for complex disassembly, we carried out hydrogen/deuterium exchange during Saccharomyces cerevisiae Vps4 disassembly of a chimeric Vps24-2 ESCRT-III filament. EX1 exchange behavior shows that Vps4 completely unfolds ESCRT-III substrates on a time scale consistent with the disassembly reaction. The established unfoldase ClpX showed the same pattern, thus demonstrating a common unfolding mechanism. Vps4 hexamers containing a single cysteine residue in the pore loops were cross-linked to ESCRT-III subunits containing unique cysteines within the folded core domain. These data support a mechanism in which Vps4 disassembles its substrates by completely unfolding them and threading them through the central pore.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Molecular Chaperones / metabolism*
  • Protein Folding
  • Protein Transport
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Endosomal Sorting Complexes Required for Transport
  • Molecular Chaperones
  • Saccharomyces cerevisiae Proteins
  • VPS4 protein, S cerevisiae
  • unfolding protein, S cerevisiae
  • Adenosine Triphosphatases