Structure of the Commander Endosomal Trafficking Complex Linked to X-Linked Intellectual Disability/Ritscher-Schinzel Syndrome

• DOI: 10.2139/ssrn.4330804
• Publication Date: 2023-01-31T11:30:02Z
• Authors: Michael D. Healy; Kerrie E. McNally; Rebeka Butkovic; Molly Chilton; Kohji Kato; Joanna Sacharz; Calum McConville; Edmund Moody; Shrestha Shaw; Vincente Planelle...; Sathish Yadav; Jennifer Ross; Ufuk Borucu; Catherine Palmer; Kai-En Chen; Tristan Croll; Ryan Hall; Nikeisha Caruana; Rajesh Ghai; Thi Nguyen; Kate Heesom; Shinji Saitoh; Imre Berger; Christiane Schaff...; Tom Williams; David A. Stroud; Emmanuel Derivery; Brett Collins; Peter J. Cullen
• Keywords: 0301 basic medicine; 0303 health sciences; 03 medical and health sciences

SUMMARYThe Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed of VPS35L, VPS26C and VPS29, and the CCC complex which contains ten subunits COMMD1-COMMD10 and two coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy andin silicopredictions 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 stabilised by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a sixteenth 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.