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CCeMMP Seminar Series – Prof. Brett Collins – April 2024

The Commander complex is required for endosomal recycling of diverse transmembrane cargos including the amyloid precursor protein linked to Alzheimer’s disease and is mutated in the neurodevelopmental Ritscher-Schinzel syndrome. It comprises two subassemblies; 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, cryoEM and in silico predictions, we have assembled a complete structural model of Commander [1]. 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. Prof. Collins will also discuss some of the technical challenges to solving this structure, compare his work with other cryoEM structures recently published, and describe how AlphaFold2 predictions are providing insights that are now guiding our future studies of Commander structure and function.

[1] Healy MD et al., Cell. 2023, 186(10):2219-2237.e29. doi: 10.1016/j.cell.2023.04.003. PMID: 37172566.

Prof. Brett Collins

Centre for Cell Biology of Chronic Disease,

Institute for Molecular Bioscience,

The University of Queensland