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.
Highlights
Ciliary research had a rocky trail to travel since the discovery of cilia in 1675 as the first known organelle by Antony Van Leeuwenhoek
It binds with its cargo to the intraflagellar transport (IFT) complex, a large heterooligomeric protein complex that is transported along ciliary microtubules by the molecular motors dynein and kinesin (Wingfield et al, 2018; Stepanek and Pigino, 2016)
To obtain suitable samples for high-resolution structural analysis, we chose to work on the BBSome core instead of the full complex, because the core, comprising BBS1, 4, 5, 8, 9, and 18 was considerably better soluble, more stable and homogeneous, but still bound with high affinity to Arl6 and cargo peptides (Figure 1A) (Klink et al, 2017)
Summary
Ciliary research had a rocky trail to travel since the discovery of cilia in 1675 as the first known organelle by Antony Van Leeuwenhoek. Compared to the other subunits, BBS5 is more loosely attached to the BBSome core complex, as we could only identify the subunit in a subpopulation of particles (Figure 1—figure supplements 1 and 3).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
