The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets

  1. Han Han
  2. Nicole Monroe
  3. Wesley I Sundquist  Is a corresponding author
  4. Peter S Shen  Is a corresponding author
  5. Christopher P Hill  Is a corresponding author
  1. University of Utah School of Medicine, United States

Abstract

The hexameric AAA ATPase Vps4 drives membrane fission by remodeling and disassembling ESCRT-III filaments. Building upon our earlier 4.3 Å resolution cryo-EM structure (Monroe, Han et al. 2017), we now report a 3.2 Å structure of Vps4 bound to an ESCRT-III peptide substrate. The new structure reveals that the peptide approximates a b-strand conformation whose helical symmetry matches that of the five Vps4 subunits it contacts directly. Adjacent Vps4 subunits make equivalent interactions with successive substrate dipeptides through two distinct classes of side chain binding pockets formed primarily by Vps4 pore loop 1. These pockets accommodate a wide range of residues, while main chain hydrogen bonds may help dictate substrate-binding orientation. The structure supports a 'conveyor belt' model of translocation in which ATP binding allows a Vps4 subunit to join the growing end of the helix and engage the substrate, while hydrolysis and release promotes helix disassembly and substrate release at the lagging end.

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Article and author information

Author details

  1. Han Han

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  2. Nicole Monroe

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7678-4997
  3. Wesley I Sundquist

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    wes@biochem.utah.edu
    Competing interests
    Wesley I Sundquist, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9988-6021
  4. Peter S Shen

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    peter.shen@biochem.utah.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6256-6910
  5. Christopher P Hill

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    chris@biochem.utah.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6796-7740

Funding

National Institutes of Health (P50 GM082545)

  • Han Han
  • Nicole Monroe
  • Wesley I Sundquist
  • Peter S Shen
  • Christopher P Hill

National Institutes of Health (T32 AI055434)

  • Nicole Monroe

National Institutes of Health (R37 AI051174-16)

  • Nicole Monroe
  • Wesley I Sundquist

National Institutes of Health (R01 GM112080)

  • Nicole Monroe
  • Wesley I Sundquist

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andreas Martin, University of California, Berkeley, United States

Publication history

  1. Received: August 18, 2017
  2. Accepted: November 21, 2017
  3. Accepted Manuscript published: November 22, 2017 (version 1)
  4. Version of Record published: December 5, 2017 (version 2)

Copyright

© 2017, Han et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Han Han
  2. Nicole Monroe
  3. Wesley I Sundquist
  4. Peter S Shen
  5. Christopher P Hill
(2017)
The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets
eLife 6:e31324.
https://doi.org/10.7554/eLife.31324

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