Michael D. Healy, Kerrie E. McNally, Rebeka Butkovič, Molly Chilton, Kohji Kato, Joanna Sacharz, Calum McConville, Edmund R.R. Moody, Shrestha Shaw, Vicente J. Planelles-Herrero, Sathish K.N. Yadav, Jennifer Ross, Ufuk Borucu, Catherine S. Palmer, Kai-En Chen, Tristan I. Croll, Ryan J. Hall, Nikeisha J. Caruana, Rajesh Ghai, Thi H.D. Nguyen, Kate J. Heesom, Shinji Saitoh, Imre Berger, Christiane Schaffitzel, Tom A. Williams, David A. Stroud, Emmanuel Derivery, Brett M. Collins, Peter J. Cullen

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.

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