Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Collins, B.; McConville, C.; Palmer, C.; Schaffitzel, C.; Stroud, D.; Moody, E.; Derivery, E.; Berger, I.; Ross, J.; Sacharz, J.; Chen, K.-E.; Heesom, K.; McNally, K.; Kato, K.; Healy, M.; Chilton, M.; Caruana, N.; Cullen, P.; Ghai, R.; Butkovic, R.; Hall, R.; Yadav, S.; Saitoh, S.; Shaw, S.; Nguyen, T.; Williams, T.; Croll, T.; Borucu, U.; Planelles-Herrero, V.

doi:10.1101/2023.01.25.525455

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bioRxiv · 10.1101/2023.01.25.525455

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

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Abstract

The 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 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 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.

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Collins, B., McConville, C., Palmer, C., Schaffitzel, C., Stroud, D., Moody, E., Derivery, E., Berger, I., Ross, J., Sacharz, J., Chen, K.-E., Heesom, K., McNally, K., Kato, K., Healy, M., Chilton, M., Caruana, N., Cullen, P., Ghai, R., Butkovic, R., Hall, R., Yadav, S., Saitoh, S., Shaw, S., Nguyen, T., Williams, T., Croll, T., Borucu, U., Planelles-Herrero, V.. 2023-01-26. Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome. https://doi.org/10.1101/2023.01.25.525455

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