1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations

  1. Jone Paesmans
  2. Ella Martin
  3. Babette Deckers
  4. Marjolijn Berghmans
  5. Ritika Sethi
  6. Yannick Loeys
  7. Els Pardon
  8. Jan Steyaert
  9. Patrik Verstreken
  10. Christian Galicia  Is a corresponding author
  11. Wim Versées  Is a corresponding author
  1. Vrije Universiteit Brussel, Belgium
  2. VIB-VUB, Belgium
  3. KU Leuven, Belgium
Research Article
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Cite this article as: eLife 2020;9:e64922 doi: 10.7554/eLife.64922
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Abstract

Synaptojanin1 (Synj1) is a phosphoinositide phosphatase, important in clathrin uncoating during endocytosis of presynaptic vesicles. It was identified as a potential drug target for Alzheimer's disease, Down syndrome and TBC1D24-associated epilepsy, while also loss-of-function mutations in Synj1 are associated with epilepsy and Parkinson's disease. Despite its involvement in a range of disorders, structural and detailed mechanistic information regarding the enzyme is lacking. Here, we report the crystal structure of the 5-phosphatase domain of Synj1. Moreover, we also present a structure of this domain bound to the substrate diC8-PI(3,4,5)P3, providing the first image of a 5-phosphatase with a trapped substrate in its active site. Together with an analysis of the contribution of the different inositide phosphate groups to catalysis, these structures provide new insights in the Synj1 mechanism. Finally, we analyzed the effect of three clinical missense mutations (Y793C, R800C, Y849C) on catalysis, unveiling the molecular mechanisms underlying Synj1-associated disease.

Data availability

Diffraction data have been deposited in the PDB under the accession code 7A0V and 7A17. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 4 and Figure 4 - figure supplements 1-3.

Article and author information

Author details

  1. Jone Paesmans

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3292-4609
  2. Ella Martin

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
  3. Babette Deckers

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
  4. Marjolijn Berghmans

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8699-6915
  5. Ritika Sethi

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
  6. Yannick Loeys

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
  7. Els Pardon

    Center for Structural Biology, VIB-VUB, Brussels, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2466-0172
  8. Jan Steyaert

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3825-874X
  9. Patrik Verstreken

    Department of Neurosciences, KU Leuven, Leuven, Belgium
    Competing interests
    Patrik Verstreken, Reviewing editor, eLife.
  10. Christian Galicia

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    For correspondence
    Christian.Galicia.Diaz.Santana@vub.be
    Competing interests
    No competing interests declared.
  11. Wim Versées

    Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
    For correspondence
    wim.versees@vub.be
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4695-696X

Funding

Fonds Wetenschappelijk Onderzoek (1S04918N)

  • Jone Paesmans

Fonds Wetenschappelijk Onderzoek (1S09120N)

  • Ella Martin

Fonds Wetenschappelijk Onderzoek (G0D3317N)

  • Patrik Verstreken
  • Wim Versées

Fonds Wetenschappelijk Onderzoek (11D4621N)

  • Babette Deckers

Vrije Universiteit Brussel (SRP50)

  • Wim Versées

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Axel T Brunger, Stanford University, United States

Publication history

  1. Received: November 15, 2020
  2. Accepted: December 16, 2020
  3. Accepted Manuscript published: December 22, 2020 (version 1)
  4. Version of Record published: January 4, 2021 (version 2)

Copyright

© 2020, Paesmans et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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