The Commander complex, a 16-protein assembly, plays multiple roles in cell homeostasis, cell cycle and immune response. It consists of copper-metabolism Murr1 domain proteins (COMMD1–10), coiled-coil domain-containing proteins (CCDC22 and CCDC93), DENND10 and the Retriever subcomplex (VPS26C, VPS29 and VPS35L), all expressed ubiquitously in the body and linked to various diseases. Here, we report the structure and key interactions of the endogenous human Commander complex by cryogenic-electron microscopy and mass spectrometry-based proteomics. The complex consists of a stable core of COMMD1–10 and an effector containing DENND10 and Retriever, scaffolded together by CCDC22 and CCDC93. We establish the composition of Commander and reveal major interaction interfaces. These findings clarify its roles in intracellular transport, and uncover a strong association with cilium assembly, and centrosome and centriole functions.

Commander 复合体是一个 16 蛋白组装体，在细胞稳态、细胞周期和免疫反应中发挥多种作用。它由铜代谢 Murr1 结构域蛋白 (COMMD1–10)、含卷曲螺旋结构域的蛋白（CCDC22 和 CCDC93）、DENND10 和猎犬亚复合体（VPS26C、VPS29 和 VPS35L）组成，所有这些蛋白在体内普遍表达并与各种疾病。在这里，我们通过低温电子显微镜和基于质谱的蛋白质组学报告了内源性人类指挥官复合物的结构和关键相互作用。该复合物由 COMMD1-10 的稳定核心和包含 DENND10 和 Retriever 的效应子组成，由 CCDC22 和 CCDC93 支架在一起。我们建立了Commander的组成并揭示了主要的交互接口。这些发现阐明了其在细胞内运输中的作用，并揭示了与纤毛组装、中心体和中心粒功能的密切相关性。