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

Abstract
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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 ARL6^GTP, and we describe the changes in BBSome conformation induced by ARL6^GTP 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

1. Yang S
2. Bahl K
3. Chou H-T
4. Nachury MV
5. Walz T
(2020) Cryo-EM structure of apo-BBSome
EMDB, EMD-21251.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-21251
1. Yang S
2. Bahl K
3. Chou H-T
4. Nachury MV
5. Walz T
(2020) Cryo-EM structure of apo-BBSome
Protein Data Bank, 6VNW.

http://www.rcsb.org/structure/6VNW
1. Yang S
2. Bahl K
3. Chou H-T
4. Nachury MV
5. Walz T
(2020) Cryo-EM structure of the BBSome-ARL6 complex
EMDB, EMD-21259.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-21259
1. Yang S
2. Bahl K
3. Chou H-T
4. Nachury MV
5. Walz T
(2020) Cryo-EM structure of the BBSome-ARL6 complex
Protein Data Bank, 6VOA.

http://www.rcsb.org/structure/6VOA

Article and author information

Author details

Shuang Yang

Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kriti Bahl

Department of Ophthalmology, UCSF, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Hui-Ting Chou

Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Jonathan Woodsmith

Pharmaceutical Chemistry, University of Graz, Graz, Austria

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0790-3726
Ulrich Stelzl

Pharmaceutical Chemistry, University of Graz, Graz, Austria

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2500-3585
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.

"This ORCID iD identifies the author of this article:" 0000-0003-2606-2835
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.

"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.

Copyright

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.