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

• Published in: Cell Vol. 186; no. 10; pp. 2219 - 2237.e29
• Main Authors: Healy, Michael D., McNally, Kerrie E., Butkovič, Rebeka, Chilton, Molly, Kato, Kohji, Sacharz, Joanna, McConville, Calum, Moody, Edmund R.R., Shaw, Shrestha, Planelles-Herrero, Vicente J., Yadav, Sathish K.N., Ross, Jennifer, Borucu, Ufuk, Palmer, Catherine S., Chen, Kai-En, Croll, Tristan I., Hall, Ryan J., Caruana, Nikeisha J., Ghai, Rajesh, Nguyen, Thi H.D., Heesom, Kate J., Saitoh, Shinji, Berger, Imre, Schaffitzel, Christiane, Williams, Tom A., Stroud, David A., Derivery, Emmanuel, Collins, Brett M., Cullen, Peter J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.05.2023; Cell Press
• Subjects: Abnormalities, Multiple; AlphaFold; CCC complex; CCDC22; CCDC93; Commander; COMMD; Craniofacial Abnormalities; DENND10; Endosome; Endosomes - metabolism; Humans; Multiprotein Complexes - metabolism; Protein Transport; Proteins - metabolism; Retriever; Retromer; Ritscher-Schinzel syndrome; VPS29; VPS29; Retriever; Commander; AlphaFold; DENND10; CCC complex; CCDC22; COMMD; Endosome; CCDC93; Retromer; Ritscher-Schinzel syndrome
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.04.003

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. [Display omitted] •CryoEM, crystal and modeled structure of the trimeric Retriever complex•Crystal and CryoEM structures of the CCC complex•Model and functional validation of the holo-Commander complex•Disease-causing mutations in Commander perturb stability and subunit interactions Complete structural model and functional validation of the sixteen-subunit human Commander complex reveals mechanisms of assembly and how mutations causing Ritscher-Schinzel syndrome perturb stability and subunit interactions of this evolutionarily conserved trafficking machinery.