Nov 20, 2019

Structure and activation mechanism of the BBSome membrane-protein trafficking complex

BioRxiv : the Preprint Server for Biology
Alan BrownMatthew CJ Yip

Abstract

Bardet-Biedl syndrome (BBS) is an 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 master 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 key subunit implicated in substrate recognition, which widens a central cavity of the BBSome. Structural mapping of disease-causing mutations suggests that pathogenesis predominantly results from disruption of autoinhibition and activation.

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Mentioned in this Paper

Pathogenesis
Membrane of Cilium
Arl3 protein, Drosophila
BBS1 gene
Proteome
Electron Microscopy
Signal Pathways
BBS1
Structure
Recognition (Psychology)

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