Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes

  1. Shuang Yang
  2. Kriti Bahl
  3. Hui-Ting Chou
  4. Jonathan Woodsmith
  5. Ulrich Stelzl
  6. Thomas Walz  Is a corresponding author
  7. Maxence V Nachury  Is a corresponding author
  1. Rockefeller University, United States
  2. UCSF, United States
  3. University of Graz, Austria

Abstract

Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to be recognized by the BBSome.

Data availability

Structural data have been deposited into the Worldwide Protein Data Bank (wwPDB) and the Electron Microscopy Data Bank (EMDB). The EM density map for the BBSome has been deposited under accession code EMD-21251 and the EM density map for the BBSome-ARL6 complex has been deposited under accession code EMD-21259. The corresponding atomic models have been deposited under accession codes 6VNW and 6VOA.

The following data sets were generated

Article and author information

Author details

  1. Shuang Yang

    Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kriti Bahl

    Department of Ophthalmology, UCSF, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hui-Ting Chou

    Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan Woodsmith

    Pharmaceutical Chemistry, University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0790-3726
  5. Ulrich Stelzl

    Pharmaceutical Chemistry, University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2500-3585
  6. Thomas Walz

    Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, United States
    For correspondence
    twalz@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2606-2835
  7. Maxence V Nachury

    Department of Ophthalmology, UCSF, San Francisco, United States
    For correspondence
    maxence.nachury@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4918-1562

Funding

National Institute of General Medical Sciences (R01-GM089933)

  • Maxence V Nachury

Research to Prevent Blindness (Stein Innovator Award A131667)

  • Maxence V Nachury

National Eye Institute (R01- EY031462)

  • Thomas Walz
  • Maxence V Nachury

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

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: February 12, 2020
  2. Accepted: June 8, 2020
  3. Accepted Manuscript published: June 8, 2020 (version 1)
  4. Version of Record published: June 23, 2020 (version 2)

Copyright

© 2020, Yang 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. Shuang Yang
  2. Kriti Bahl
  3. Hui-Ting Chou
  4. Jonathan Woodsmith
  5. Ulrich Stelzl
  6. Thomas Walz
  7. Maxence V Nachury
(2020)
Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes
eLife 9:e55954.
https://doi.org/10.7554/eLife.55954
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