Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A

Anna Scott, Jason Gaspar, Melissa D. Stuchell-Brereton, Steven L. Alam, Jack J. Skalicky, Wesley I. Sundquist

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


The VPS4 AAA ATPases function both in endosomal vesicle formation and in the budding of many enveloped RNA viruses, including HIV-1. VPS4 proteins act by binding and catalyzing release of the membrane-associated ESCRT-III protein lattice, thereby allowing multiple rounds of protein sorting and vesicle formation. Here, we report the solution structure of the N-terminal VPS4A microtubule interacting and transport (MIT) domain and demonstrate that the VPS4A MIT domain binds the C-terminal half of the ESCRT-III protein, CHMP1B (Kd = 20 ± 13 μM). The MIT domain forms an asymmetric three-helix bundle that resembles the first three helices in a tetratricopeptide repeat (TPR) motif. Unusual interhelical interactions are mediated by a series of conserved aromatic residues that form coiled-coil interactions between the second two helices and also pack against the conserved alanines that interdigitate between the first two helices. Mutational analyses revealed that a conserved leucine residue (Leu-64) on the third helix that would normally bind the fourth helix in an extended TPR is used to bind CHMP1B, raising the possibility that ESCRT-III proteins may bind by completing the TPR motif.

Original languageEnglish
Pages (from-to)13813-13818
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 27 2005


  • Budding
  • HIV
  • Multivesicular body
  • NMR
  • Vacuolar protein sorting


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