Structural basis for ESCRT-III protein autoinhibition

Nat Struct Mol Biol. 2009 Jul;16(7):754-62. doi: 10.1038/nsmb.1621. Epub 2009 Jun 14.

Abstract

Endosomal sorting complexes required for transport-III (ESCRT-III) subunits cycle between two states: soluble monomers and higher-order assemblies that bind and remodel membranes during endosomal vesicle formation, midbody abscission and enveloped virus budding. Here we show that the N-terminal core domains of increased sodium tolerance-1 (IST1) and charged multivesicular body protein-3 (CHMP3) form equivalent four-helix bundles, revealing that IST1 is a previously unrecognized ESCRT-III family member. IST1 and its ESCRT-III binding partner, CHMP1B, both form higher-order helical structures in vitro, and IST1-CHMP1 interactions are required for abscission. The IST1 and CHMP3 structures also reveal that equivalent downstream alpha5 helices can fold back against the core domains. Mutations within the CHMP3 core-alpha5 interface stimulate the protein's in vitro assembly and HIV-inhibition activities, indicating that dissociation of the autoinhibitory alpha5 helix from the core activates ESCRT-III proteins for assembly at membranes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • Cytokinesis / physiology
  • Dimerization
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / metabolism
  • Humans
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Oncogene Proteins / chemistry*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Protein Conformation*
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Vesicular Transport Proteins / chemistry*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • CHMP1B protein, human
  • CHMP3 protein, human
  • Endosomal Sorting Complexes Required for Transport
  • Multiprotein Complexes
  • OLC1 protein, human
  • Oncogene Proteins
  • Protein Subunits
  • Recombinant Proteins
  • Vesicular Transport Proteins

Associated data

  • PDB/3FRR
  • PDB/3FRS
  • PDB/3FRT
  • PDB/3FRV