The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation

Abstract

Fusion of intracellular trafficking vesicles is mediated by the assembly of SNARE proteins into membrane-bridging complexes. SNARE-mediated membrane fusion requires Sec1/Munc18-family (SM) proteins, SNARE chaperones that can function as templates to catalyze SNARE complex assembly. Paradoxically, the SM protein Munc18-1 traps the Qa-SNARE protein syntaxin-1 in an autoinhibited closed conformation. Here we present the structure of a second SM–Qa-SNARE complex, Vps45–Tlg2. Strikingly, Vps45 holds Tlg2 in an open conformation, with its SNARE motif disengaged from its Habc domain and its linker region unfolded. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Although Tlg2 has a pronounced tendency to form homo-tetramers, Vps45 can rescue Tlg2 tetramers into stoichiometric Vps45–Tlg2 complexes. Our findings demonstrate that SM proteins can engage Qa-SNAREs using at least two different modes, one in which the SNARE is closed and one in which it is open.

Data availability

Diffraction data have been deposited in the PDB under the accession codes 6XJL, 6XMD, and 6XM1.

The following data sets were generated

Article and author information

Author details

  1. Travis J Eisemann

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Frederick Allen

    Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2969-8137
  3. Kelly Lau

    Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Gregory R Shimamura

    Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2104-5518
  5. Philip D Jeffrey

    Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Frederick M Hughson

    Molecular Biology, Princeton University, Princeton, United States
    For correspondence
    hughson@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4057-0281

Funding

National Institutes of Health (R01GM071574)

  • Frederick M Hughson

National Institutes of Health (T32GM007388)

  • Gregory R Shimamura

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

Reviewing Editor

  1. Axel T Brunger, Stanford University, United States

Publication history

  1. Received: July 4, 2020
  2. Accepted: August 15, 2020
  3. Accepted Manuscript published: August 17, 2020 (version 1)
  4. Version of Record published: September 3, 2020 (version 2)

Copyright

© 2020, Eisemann 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. Travis J Eisemann
  2. Frederick Allen
  3. Kelly Lau
  4. Gregory R Shimamura
  5. Philip D Jeffrey
  6. Frederick M Hughson
(2020)
The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation
eLife 9:e60724.
https://doi.org/10.7554/eLife.60724

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