The BBSome is a heterooctameric protein complex that plays a central role in primary cilia homeostasis. Its malfunction causes the severe ciliopathy Bardet-Biedl syndrome (BBS). The complex acts as a cargo adapter that recognizes signaling proteins such as GPCRs and links them to the intraflagellar transport machinery. The underlying mechanism is poorly understood. Here we present a high-resolution cryo-EM structure of a human heterohexameric core subcomplex of the BBSome. The structure reveals the architecture of the complex in atomic detail. It explains how the subunits interact with each other and how disease-causing mutations hamper this interaction. The complex adopts a conformation that is open for binding to membrane-associated GTPase Arl6 and a large positively charged patch likely strengthens the interaction with the membrane. A prominent negatively charged cleft at the center of the complex is likely involved in binding of positively charged signaling sequences of cargo proteins.

中文翻译：

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人类BBSome核心复合体的结构

BBSome是一种杂八聚体蛋白复合物，在原发性纤毛稳态中起着核心作用。它的故障会导致严重的纤毛病Bardet-Biedl综合征（BBS）。该复合物充当货物衔接子，可识别信号蛋白（例如GPCR）并将其链接至鞭毛内运输工具。根本的机制了解甚少。在这里，我们提出了BBSome的人类异六聚体核心亚复合体的高分辨率冷冻EM结构。该结构从原子细节上揭示了复合物的体系结构。它解释了亚基之间如何相互作用以及致病突变如何阻碍这种相互作用。该复合物采用的构象是开放的，可与膜相关的GTPase Arl6结合，并且较大的带正电荷的贴剂可能会增强与膜的相互作用。