Author:
Healy Michael D.,McNally Kerrie E.,Butkovic 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.
Abstract
SUMMARYThe 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 andin silicopredictions 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.
Publisher
Cold Spring Harbor Laboratory