Structure and Interactions of the Endogenous Human Commander Complex

Abstract

Abstract The Commander complex, a 16-protein assembly, plays multiple roles in cell homeostasis, cell cycle, and immune response. It consists of COMMD1-10, CCDC22, CCDC93, DENND10, and the Retriever sub-complex (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.