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).
-
Human BBSome complex (subunits 1,4,8,9,18)Protein Data Bank, 6XT9.
-
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.
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.
Metrics
-
- 4,339
- views
-
- 623
- downloads
-
- 67
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Structure of the human BBSome core complex
eLife 9:e53910.
https://doi.org/10.7554/eLife.53910
Further reading
-
- 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.
-
- Structural Biology and Molecular Biophysics
Transition-state (TS) theory has provided the theoretical framework to explain the enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles of conformations, unique TSs would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied the nature of the enzymatic TS for the phosphoryl-transfer step in adenylate kinase by quantum-mechanics/molecular-mechanics calculations. We find a structurally wide set of energetically equivalent configurations that lie along the reaction coordinate and hence a broad transition-state ensemble (TSE). A conformationally delocalized ensemble, including asymmetric TSs, is rooted in the macroscopic nature of the enzyme. The computational results are buttressed by enzyme kinetics experiments that confirm the decrease of the entropy of activation predicted from such wide TSE. TSEs as a key for efficient enzyme catalysis further boosts a unifying concept for protein folding and conformational transitions underlying protein function.
