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Structure of the membrane-assembled retromer coat determined by cryo-electron tomography

Author

Listed:
  • Oleksiy Kovtun

    (Cambridge Biomedical Campus
    European Molecular Biology Laboratory)

  • Natalya Leneva

    (The University of Queensland
    University of Cambridge)

  • Yury S. Bykov

    (Cambridge Biomedical Campus
    European Molecular Biology Laboratory)

  • Nicholas Ariotti

    (The University of Queensland
    Electron Microscope Unit, The University of New South Wales)

  • Rohan D. Teasdale

    (The University of Queensland
    School of Biomedical Sciences, The University of Queensland)

  • Miroslava Schaffer

    (Max Planck Institute of Biochemistry)

  • Benjamin D. Engel

    (Max Planck Institute of Biochemistry)

  • David. J. Owen

    (University of Cambridge)

  • John A. G. Briggs

    (Cambridge Biomedical Campus
    European Molecular Biology Laboratory)

  • Brett M. Collins

    (The University of Queensland)

Abstract

Eukaryotic cells traffic proteins and lipids between different compartments using protein-coated vesicles and tubules. The retromer complex is required to generate cargo-selective tubulovesicular carriers from endosomal membranes1–3. Conserved in eukaryotes, retromer controls the cellular localization and homeostasis of hundreds of transmembrane proteins, and its disruption is associated with major neurodegenerative disorders4–7. How retromer is assembled and how it is recruited to form coated tubules is not known. Here we describe the structure of the retromer complex (Vps26–Vps29–Vps35) assembled on membrane tubules with the bin/amphiphysin/rvs-domain-containing sorting nexin protein Vps5, using cryo-electron tomography and subtomogram averaging. This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the ‘legs’ of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. The bases of the arches connect to each other and to Vps5 through Vps26, and the presence of the same arches on coated tubules within cells confirms their functional importance. Vps5 binds to Vps26 at a position analogous to the previously described cargo- and Snx3-binding site, which suggests the existence of distinct retromer-sorting nexin assemblies. The structure provides insight into the architecture of the coat and its mechanism of assembly, and suggests that retromer promotes tubule formation by directing the distribution of sorting nexin proteins on the membrane surface while providing a scaffold for regulatory-protein interactions.

Suggested Citation

  • Oleksiy Kovtun & Natalya Leneva & Yury S. Bykov & Nicholas Ariotti & Rohan D. Teasdale & Miroslava Schaffer & Benjamin D. Engel & David. J. Owen & John A. G. Briggs & Brett M. Collins, 2018. "Structure of the membrane-assembled retromer coat determined by cryo-electron tomography," Nature, Nature, vol. 561(7724), pages 561-564, September.
  • Handle: RePEc:nat:nature:v:561:y:2018:i:7724:d:10.1038_s41586-018-0526-z
    DOI: 10.1038/s41586-018-0526-z
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    Cited by:

    1. Casper Berger & Maud Dumoux & Thomas Glen & Neville B.-y. Yee & John M. Mitchels & Zuzana Patáková & Michele C. Darrow & James H. Naismith & Michael Grange, 2023. "Plasma FIB milling for the determination of structures in situ," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Arthur A. Melo & Thiemo Sprink & Jeffrey K. Noel & Elena Vázquez-Sarandeses & Chris Hoorn & Saif Mohd & Justus Loerke & Christian M. T. Spahn & Oliver Daumke, 2022. "Cryo-electron tomography reveals structural insights into the membrane remodeling mode of dynamin-like EHD filaments," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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