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 b-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.

中文翻译：

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BBSome膜蛋白运输复合物的结构和激活机制

Bardet-Biedl综合征（BBS）是由于无法正确建立或维持纤毛依赖性信号传导通路而导致的目前无法治愈的纤毛病。与BBS相关的八种蛋白质组装成BBSome，BBSome是睫状膜蛋白质组的关键调节因子。我们报告了在非活动状态和活动状态分别为3.1和3.5Å分辨率的天然牛BBSome的电子低温显微镜（cryo-EM）结构。在活跃状态下，BBSome与Arf家族GTPase（ARL6 / BBS3）结合，后者将BBSome募集到睫状膜上。ARL6识别由BBS1和BBS7形成的复合结合位点，该位点在非活性状态下被封闭。激活需要BBS1的b螺旋结构域的意外旋转，BBS1是最常与底物识别相关的亚基，从而扩大了BBSome的中心腔。