Structure and activation mechanism of the BBSome membrane protein trafficking complex.
Bardet-Biedl syndrome (BBS) is a currently 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 key 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 β-propeller domain of BBS1, the subunit most frequently implicated in substrate recognition, which widens a central cavity of the BBSome. Structural mapping of disease-causing mutations suggests that pathogenesis results from folding defects and the disruption of autoinhibition and activation.
['Singh|Sandeep K|SK|', 'Gui|Miao|M|', 'Koh|Fujiet|F|', 'Yip|Matthew Cj|MC|0000-0002-2505-9987', 'Brown|Alan|A|0000-0002-0021-0476']
D020727:ADP-Ribosylation Factors D000818:Animals D020788:Bardet-Biedl Syndrome D002417:Cattle D002923:Cilia D020285:Cryoelectron Microscopy D006801:Humans D008565:Membrane Proteins D011485:Protein Binding D011487:Protein Conformation D000072417:Protein Domains D021381:Protein Transport
BBSome protein trafficking cryo-EM Bos taurus cilia intraflagellar transport molecular biophysics structural biology