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

  • Cell. 2023 May 11;186(10):2219-2237.e29. doi: 10.1016/j.cell.2023.04.003.
Michael D Healy  1 ,  Kerrie E McNally  2 ,  Rebeka Butkovič  3 ,  Molly Chilton  3 ,  Kohji Kato  3 ,  Joanna Sacharz  4 ,  Calum McConville  4 ,  Edmund R R Moody  5 ,  Shrestha Shaw  3 ,  Vicente J Planelles-Herrero  6 ,  Sathish K N Yadav  3 ,  Jennifer Ross  3 ,  Ufuk Borucu  3 ,  Catherine S Palmer  4 ,  Kai-En Chen  1 ,  Tristan I Croll  7 ,  Ryan J Hall  1 ,  Nikeisha J Caruana  8 ,  Rajesh Ghai  1 ,  Thi H D Nguyen  6 ,  Kate J Heesom  9 ,  Shinji Saitoh  10 ,  Imre Berger  11 ,  Christiane Schaffitzel  3 ,  Tom A Williams  5 ,  David A Stroud  12 ,  Emmanuel Derivery  6 ,  Brett M Collins  13 ,  Peter J Cullen  14
Affiliations
  • 1. Centre for Cell Biology of Chronic Disease, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
  • 2. School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK; MRC Laboratory of Molecular Biology, CB2 0QH Cambridge, UK. Electronic address: [email protected].
  • 3. School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK.
  • 4. Department of Biochemistry and Pharmacology, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
  • 5. School of Biological Sciences, University of Bristol, BS8 1TD Bristol, UK.
  • 6. MRC Laboratory of Molecular Biology, CB2 0QH Cambridge, UK.
  • 7. Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, UK.
  • 8. Department of Biochemistry and Pharmacology, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia; Institute of Health and Sport (iHeS), Victoria University, Melbourne, VIC Australia.
  • 9. Proteomics Facility, School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK.
  • 10. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan.
  • 11. School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK; Max Planck Bristol Centre for Minimal Biology, Department of Chemistry, University of Bristol, BS8 1TS Bristol, UK.
  • 12. Department of Biochemistry and Pharmacology, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC Australia.
  • 13. Centre for Cell Biology of Chronic Disease, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: [email protected].
  • 14. School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK. Electronic address: [email protected].
PMID: 37172566 DOI: 10.1016/j.cell.2023.04.003
Abstract

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.

Keywords
AlphaFold; CCC complex; CCDC22; CCDC93; COMMD; Commander; DENND10; Endosome; Retriever; Retromer; Ritscher-Schinzel syndrome; VPS29.