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

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 NguyenKate J Heesom, Shinji Saitoh, Imre Berger, Christiane Schaffitzel, Tom A Williams, David A Stroud, Emmanuel Derivery, Brett M Collins, Peter J Cullen

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

44 Citations (SciVal)

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.

Original language	English
Journal	Cell
Volume	186
Issue number	10
Early online date	11 May 2023
DOIs	https://doi.org/10.1016/j.cell.2023.04.003
Publication status	Published - 11 May 2023

Data Availability Statement

• Coordinates for the COMMD1-10/CCDC22/CCDC93 complex have been deposited at the Protein DataBank (PDB) with accession codes 8F2R (CryoSPARC) and 8F2U (Relion) with respective Electron Microscopy DataBank under accession codes EMD-28825 (CryoSPARC) and EMD-28827 (Relion). Coordinates and structure factors for the crystal structure of the COMMD5-COMMD10-COMMD9-COMMD7 complex have been deposited at the PDB with accession code 8ESD. Coordinates and structure factors for the crystal structure of the VPS29-VPS35L peptide complex have been deposited at the PDB with accession code 8ESE. All datasets are publicly available as of the date of the publication.
• Predicted structures of the Commander complex and sub-assemblies using AlphaFold2 have been deposited in the ModelArchive (https://www.modelarchive.org) with accession numbers as outlined in the key resources table. All datasets are publicly available as of the date of the publication.
• This paper does not report original code.
• Any additional information and all the relevant raw data required to reanalyze the data reported in this paper is available from the lead contact upon request.

Funding

We thank the Wolfson Bioimaging Facility, Proteomics Facility, and GW4 Facility for Electron Cryo-Microscopy funded by the Wellcome Trust (202904/Z/16/Z and 206181/Z/17/Z) and BBSRC (BB/R000484/1) at the University of Bristol, and the Advanced Computing Research Centre. We acknowledge the Medical Research Council (MRC) - LMB Electron Microscopy Facility for EM sample preparation and data collection and thank Jake Grimmett and Toby Darling for their support. We acknowledge the Bio21 Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation and technical support. We thank Dr. Alun Jones (IMB, UQ) for assistance with mass spectrometry and the University of Queensland Remote Operation Crystallization and X-ray (UQ ROCX) Facility and Dr. Kasun Athukorala Arachchige for protein crystallization. X-ray data were collected on the MX2 microfocus beamline at the Australian Synchrotron. We thank Dr. Andrew Carter (MRC-LMB) for suggesting biGbac. P.J.C. is supported by the Wellcome Trust (104568/Z/14/Z and 220260/Z/20/Z), the MRC (MR/L007363/1 and MR/P018807/1), the Lister Institute of Preventive Medicine, and the Royal Society Noreen Murray Research Professorship (RSRP/R1/211004). B.M.C. is supported by an Investigator Grant, Senior Research Fellowship and Project Grant from the National Health and MRC (APP2016410, APP1136021 and APP1156493). D.A.S. is supported by an Investigator Fellowship and Project Grant from the National Health and MRC (APP2009732 and APP1156732). K.E.M. is supported by the Wellcome Trust through a Sir Henry Wellcome Postdoctoral Fellowship (220480/Z/20/Z). M.D.H. was supported by the AINSE PGRA, and R.B. and S. Shaw. were supported by the EndoConnect European Research Training Network (No. 953489). C.S. and I.B. are Investigators of the Wellcome Trust (210701/Z/18/Z; 106115/Z/14/Z). T.A.W. is supported by a Royal Society University Research Fellowship (URF/R/201024) and the Moore Foundation. E.D. is funded by the MRC (MC_UP_1201/13) and Human Frontier Science Program (Career Development Award CDA00034/2017). We also thank Milot Mirdita, Sergey Ovchinnikov, Martin Steinegger, and the Colab-Fold team for making their AlphaFold2 modeling pipeline publicly available.

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Healy, M. D., McNally, K. E., Butkovič, R., Chilton, M., Kato, K., Sacharz, J., McConville, C., Moody, E. R. R., Shaw, S., Planelles-Herrero, V. J., Yadav, S. K. N., Ross, J., Borucu, U., Palmer, C. S., Chen, K.-E., Croll, T. I., Hall, R. J., Caruana, N. J., Ghai, R., ... Cullen, P. J. (2023). Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome. Cell, 186(10). https://doi.org/10.1016/j.cell.2023.04.003

Healy, MD, McNally, KE, Butkovič, R, Chilton, M, Kato, K, Sacharz, J, McConville, C, Moody, ERR, Shaw, S, Planelles-Herrero, VJ, Yadav, SKN, Ross, J, Borucu, U, Palmer, CS, Chen, K-E, Croll, TI, Hall, RJ, Caruana, NJ, Ghai, R, Nguyen, THD, Heesom, KJ, Saitoh, S, Berger, I, Schaffitzel, C, Williams, TA, Stroud, DA, Derivery, E, Collins, BM & Cullen, PJ 2023, 'Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome', Cell, vol. 186, no. 10. https://doi.org/10.1016/j.cell.2023.04.003

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title = "Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome",

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.",

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AU - Healy, Michael D

AU - McNally, Kerrie E

AU - Butkovič, Rebeka

AU - Chilton, Molly

AU - Kato, Kohji

AU - Sacharz, Joanna

AU - McConville, Calum

AU - Moody, Edmund R R

AU - Shaw, Shrestha

AU - Planelles-Herrero, Vicente J

AU - Yadav, Sathish K N

AU - Ross, Jennifer

AU - Borucu, Ufuk

AU - Palmer, Catherine S

AU - Chen, Kai-En

AU - Croll, Tristan I

AU - Hall, Ryan J

AU - Caruana, Nikeisha J

AU - Ghai, Rajesh

AU - Nguyen, Thi H D

AU - Heesom, Kate J

AU - Saitoh, Shinji

AU - Berger, Imre

AU - Schaffitzel, Christiane

AU - Williams, Tom A

AU - Stroud, David A

AU - Derivery, Emmanuel

AU - Collins, Brett M

AU - Cullen, Peter J

PY - 2023/5/11

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N2 - 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.

AB - 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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VL - 186

JO - Cell

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ER -

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

Abstract

Data Availability Statement

Funding

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