Structure and activation mechanism of the BBSome membrane protein trafficking complex

  1. Sandeep K Singh
  2. Miao Gui
  3. Fujiet Koh
  4. Matthew CJ Yip
  5. Alan Brown  Is a corresponding author
  1. Harvard Medical School, United States

Abstract

Bardet-Biedl syndrome (BBS) is a currently incurable ciliopathy caused by the failure to correctly establish or maintain cilia-dependent signaling pathways. Eight proteins associated with BBS assemble into the BBSome, a key regulator of the ciliary membrane proteome. We report the electron cryomicroscopy (cryo-EM) structures of the native bovine BBSome in inactive and active states at 3.1 ­and 3.5 Å resolution, respectively. In the active state, the BBSome is bound to an Arf-family GTPase (ARL6/BBS3) that recruits the BBSome to ciliary membranes. ARL6 recognizes a composite binding site formed by BBS1 and BBS7 that is occluded in the inactive state. Activation requires an unexpected swiveling of the b-propeller domain of BBS1, the subunit most frequently implicated in substrate recognition, which widens a central cavity of the BBSome. Structural mapping of disease-causing mutations suggests that pathogenesis results from folding defects and the disruption of autoinhibition and activation.

Data availability

The EM density map for the BBSome has been deposited under accession code EMD-21144 and the EM density map for the BBSome:ARL6:GTP complex has been deposited under accession code EMD-21145. Masks and maps from multibody refinement are included as additional maps in these depositions. The corresponding atomic models have been deposited under accession codes 6VBU and 6VBV.

The following data sets were generated

Article and author information

Author details

  1. Sandeep K Singh

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Miao Gui

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Fujiet Koh

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    Fujiet Koh, is affiliated with Thermo Fisher Scientific. The author has no financial interests to declare.
  4. Matthew CJ Yip

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2505-9987
  5. Alan Brown

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    alan_brown@hms.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0021-0476

Funding

Pew Charitable Trusts

  • Alan Brown

Internal Retinal Research Foundation

  • Alan Brown

E. Matilda Ziegler Foundation for the Blind

  • Alan Brown

Richard and Susan Smith Family Foundation

  • Alan Brown

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: November 4, 2019
  2. Accepted: January 6, 2020
  3. Accepted Manuscript published: January 15, 2020 (version 1)
  4. Version of Record published: February 13, 2020 (version 2)

Copyright

© 2020, Singh 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. Sandeep K Singh
  2. Miao Gui
  3. Fujiet Koh
  4. Matthew CJ Yip
  5. Alan Brown
(2020)
Structure and activation mechanism of the BBSome membrane protein trafficking complex
eLife 9:e53322.
https://doi.org/10.7554/eLife.53322
  1. Further reading

Further reading

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