Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome

Michael D Healy,et al.

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.