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Title | Structure and activation mechanism of the BBSome membrane protein trafficking complex. |
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Journal, issue, pages | Elife, Vol. 9, Year 2020 |
Publish date | Jan 15, 2020 |
Authors | Sandeep K Singh / Miao Gui / Fujiet Koh / Matthew Cj Yip / Alan Brown / |
PubMed Abstract | 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 ...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. |
External links | Elife / PubMed:31939736 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.1 - 3.5 Å |
Structure data | EMDB-21144, PDB-6vbu: EMDB-21145, PDB-6vbv: |
Chemicals | ChemComp-CA: ChemComp-GTP: |
Source |
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Keywords | PROTEIN TRANSPORT / Cilia / ciliopathy / complex / membrane-protein transport |