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bioRxiv · 10.1101/849877

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

Brown, A.·Singh, S. K.·Gui, M.·Koh, F.·Yip, M. C.
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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 [A] 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 {beta}-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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Brown, A., Singh, S. K., Gui, M., Koh, F., Yip, M. C.. 2019-11-20. Structure and activation mechanism of the BBSome membrane-protein trafficking complex. https://doi.org/10.1101/849877

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