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

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

doi:10.1016/j.cell.2023.04.003

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.

Authors

Michael D Healy¹, Kerrie E McNally², Rebeka Butkovič³, Molly Chilton³, Kohji Kato³, Joanna Sacharz⁴, Calum McConville⁴, Edmund R R Moody⁵, Shrestha Shaw³, Vicente J Planelles-Herrero⁶, Sathish K N Yadav³, Jennifer Ross³, Ufuk Borucu³, Catherine S Palmer⁴, Kai-En Chen¹, Tristan I Croll⁷, Ryan J Hall¹, Nikeisha J Caruana⁸, Rajesh Ghai¹, Thi H D Nguyen⁶, Kate J Heesom⁹, Shinji Saitoh¹⁰, Imre Berger¹¹, Christiane Schaffitzel³, Tom A Williams⁵, David A Stroud¹², Emmanuel Derivery⁶, Brett M Collins¹³, Peter J Cullen¹⁴

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: kmcnally@mrc-lmb.cam.ac.uk.
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: b.collins@imb.uq.edu.au.
¹⁴ School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, UK. Electronic address: pete.cullen@bristol.ac.uk.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple*
Craniofacial Abnormalities*
Endosomes / metabolism
Humans
Multiprotein Complexes* / metabolism
Protein Transport
Proteins / metabolism

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

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