Dr Michael Healy | Unravelling the Molecular Architecture of the Commander Complex

4 April 2024, 1.00 PM - 4 April 2024, 2.00 PM

Dr Michael Healy, University of Queensland

C42 Lecture Theatre, Biomedical Sciences Building

Abstract: The highly conserved Commander complex is required for endosomal recycling of diverse transmembrane cargo and mutations cause 3C/Ritscher-Schinzel (RSS) syndrome. It is formed from two subassemblies called i) Retriever, a trimer of VPS35L, VPS26C and VPS29, and the ii) CCC complex containing two coiled-coil domain-containing proteins CCDC22 and CCDC93 and the ten subunits COMMD1-10 from the Copper Metabolism Murr1 Domain (COMMD) family. Combining X-ray crystallography, cryoelectron microscopy and in scilico modelling we have determined the overall structure of Commander. Retriever forms an extended structure, like Retromer, but with distinct characteristics that prevent the shared VPS29 subunit from interacting with Retromer-associated factors. The ten COMMD proteins form an interwoven decameric ring, with a specific subunit organisation that mediates extensive interactions with CCDC N-terminal regions. CCDC22 and CCDC93 form a dimeric coiled-coil that bridges between the COMMD and Retriever assemblies and provide an additional platform for interaction with the DENND10 subunit, resulting in a highly conserved overall complex with a V-shaped architecture. The structure explains the impact of disease-causing mutations and begins to reveal the molecular signatures required for functional assembly of this trafficking machinery.


Host: Pete Cullen

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Alan Cheung

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