Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding

Dev Cell. 2008 Jul;15(1):62-73. doi: 10.1016/j.devcel.2008.05.014.


The ESCRT pathway mediates membrane remodeling during enveloped virus budding, cytokinesis, and intralumenal endosomal vesicle formation. Late in the pathway, a subset of membrane-associated ESCRT-III proteins display terminal amphipathic "MIM1" helices that bind and recruit VPS4 ATPases via their MIT domains. We now report that VPS4 MIT domains also bind a second, "MIM2" motif found in a different subset of ESCRT-III subunits. The solution structure of the VPS4 MIT-CHMP6 MIM2 complex revealed that MIM2 elements bind in extended conformations along the groove between the first and third helices of the MIT domain. Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. MIT-MIM2 interactions appear to be common throughout the ESCRT pathway and possibly elsewhere, and we suggest how these interactions could contribute to a mechanism in which VPS4 and ESCRT-III proteins function together to constrict the necks of budding vesicles.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Biosensing Techniques
  • Conserved Sequence
  • HIV-1 / metabolism*
  • Humans
  • Lysosomes / metabolism*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Transport
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Spectrum Analysis, Raman
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*


  • Recombinant Proteins
  • Vesicular Transport Proteins
  • Adenosine Triphosphatases