Structure of the human BBSome core complex
- Max Planck Institute of Molecular Physiology, Germany
Abstract
The BBSome is a heterooctameric protein complex that plays a central role in primary cilia homeostasis. Its malfunction causes the severe ciliopathy Bardet-Biedl syndrome (BBS). The complex acts as a cargo adapter that recognizes signaling proteins such as GPCRs and links them to the intraflagellar transport machinery. The underlying mechanism is poorly understood. Here we present a high-resolution cryo-EM structure of a human heterohexameric core subcomplex of the BBSome. The structure reveals the architecture of the complex in atomic detail. It explains how the subunits interact with each other and how disease-causing mutations hamper this interaction. The complex adopts a conformation that is open for binding to membrane-associated GTPase Arl6 and a large positively charged patch likely strengthens the interaction with the membrane. A prominent negatively charged cleft at the center of the complex is likely involved in binding of positively charged signaling sequences of cargo proteins.
Data availability
The electron density maps have been deposited to the EMDB under the accession codes EMD-10617 and EMD-10618. The final models of the BBSome were submitted to the Protein Data Bank under the accession codes 6XT9 (subunits BBS1,4,8,9,18) and 6XTB (subunits BBS1,4,5,8,9,18).
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Human BBSome complex (subunits 1,4,8,9,18)Protein Data Bank, 6XT9.
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Human BBSome complex (subunits 1,4,8,9,18 and 5)Protein Data Bank, 6XTB.
Article and author information
Author details
Christos Gatsogiannis
Alfred Wittinghofer
Funding
Max-Planck-Gesellschaft
- Stefan Raunser
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom
Publication history
- Received: November 25, 2019
- Accepted: January 15, 2020
- Accepted Manuscript published: January 17, 2020 (version 1)
- Version of Record published: February 13, 2020 (version 2)
Copyright
© 2020, Klink 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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Structure of the human BBSome core complex
eLife 9:e53910.
https://doi.org/10.7554/eLife.53910
Further reading
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- Structural Biology and Molecular Biophysics
The structures of the bovine and human BBSome reveal that a conformational change is required to recruit the complex to the ciliary membrane.
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- Structural Biology and Molecular Biophysics
Formation of membraneless organelles or biological condensates via phase separation and related processes hugely expands the cellular organelle repertoire. Biological condensates are dense and viscoelastic soft matters instead of canonical dilute solutions. To date, numerous different biological condensates have been discovered; but mechanistic understanding of biological condensates remains scarce. In this study, we developed an adaptive single molecule imaging method that allows simultaneous tracking of individual molecules and their motion trajectories in both condensed and dilute phases of various biological condensates. The method enables quantitative measurements of concentrations, phase boundary, motion behavior and speed of molecules in both condensed and dilute phases as well as the scale and speed of molecular exchanges between the two phases. Notably, molecules in the condensed phase do not undergo uniform Brownian motion, but instead constantly switch between a (class of) confined state(s) and a random diffusion-like motion state. Transient confinement is consistent with strong interactions associated with large molecular networks (i.e., percolation) in the condensed phase. In this way, molecules in biological condensates behave distinctly different from those in dilute solutions. The methods and findings described herein should be generally applicable for deciphering the molecular mechanisms underlying the assembly, dynamics and consequently functional implications of biological condensates.
