The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

Commander 复合物是多种跨膜货物的内体回收所必需的，并且在 Ritscher-Schinzel 综合征中发生突变。它包括两个子组件：由VPS35L、VPS26C和VPS29组成的检索器；CCC 复合体包含 12 个亚基：COMMD1-COMMD10 和含有卷曲螺旋结构域 (CCDC) 的蛋白 CCDC22 和 CCDC93。结合 X 射线晶体学、电子冷冻显微镜和计算机预测，我们组装了 Commander 的完整结构模型。Retriever与内体Retromer复合体关系较远，但具有独特的功能，可防止共享的VPS29亚基与Retromer相关因子相互作用。COMMD 蛋白形成独特的异十聚环，通过与 CCDC22 和 CCDC93 的广泛相互作用而稳定。它们采用卷曲线圈结构，连接 CCC 和猎犬组件，并招募第 16 个亚基 DENND10，形成完整的指挥官复合体。该结构可以绘制致病突变图谱，并揭示这种进化上保守的贩运机制发挥功能所需的分子特征。