Two Distinct Modes of ESCRT-III Recognition Are Required for VPS4 Functions in Lysosomal Protein Targeting and HIV-1 Budding

Collin Kieffer, Jack J. Skalicky, Eiji Morita, Ivana De Domenico, Diane M. Ward, Jerry Kaplan, Wesley I. Sundquist

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)62-73
Number of pages12
JournalDevelopmental cell
Volume15
Issue number1
DOIs
StatePublished - Jul 8 2008

Keywords

  • CELLBIO
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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