1. Neuroscience
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Autism associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses

  1. Michael Bucher
  2. Stephan Niebling
  3. Yuhao Han
  4. Dmitry Molodenskiy
  5. Fatemeh Hassani Nia
  6. Hans-Jürgen Kreienkamp
  7. Dmitri Svergun
  8. Eunjoon Kim
  9. Alla S Kostyukova
  10. Michael R Kreutz  Is a corresponding author
  11. Marina Mikhaylova  Is a corresponding author
  1. Humboldt-Universität zu Berlin, Institute of Biology, Germany
  2. European Molecular Biology Laboratory, Germany
  3. University Medical Centre Hamburg-Eppendorf, Germany
  4. Korea Advanced Institute of Science and Technology, Republic of Korea
  5. Washington State University, United States
  6. Leibniz-Institute for Neurobiology, Germany
Research Article
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Cite this article as: eLife 2021;10:e66165 doi: 10.7554/eLife.66165
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Abstract

Members of the SH3- and ankyrin-rich repeat (SHANK) protein family are considered as master scaffolds of the post-synaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Michael Bucher

    Optobiology, Humboldt-Universität zu Berlin, Institute of Biology, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Stephan Niebling

    Molecular Biophysics and High-Throughput Crystallization, European Molecular Biology Laboratory, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuhao Han

    Optobiology, Humboldt-Universität zu Berlin, Institute of Biology, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Dmitry Molodenskiy

    Biological Small Angle Scattering, European Molecular Biology Laboratory, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5954-4294
  5. Fatemeh Hassani Nia

    Institute for Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Hans-Jürgen Kreienkamp

    Institute for Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8871-9970
  7. Dmitri Svergun

    Biological Small Angle Scattering, European Molecular Biology Laboratory, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Eunjoon Kim

    Center for Synaptic Brain Dysfunctions, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Alla S Kostyukova

    The Gene and Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael R Kreutz

    RG Neuroplasticity, Leibniz-Institute for Neurobiology, Magdeburg, Germany
    For correspondence
    michael.kreutz@zmnh.uni-hamburg.de
    Competing interests
    The authors declare that no competing interests exist.
  11. Marina Mikhaylova

    Optobiology, Humboldt-Universität zu Berlin, Institute of Biology, Berlin, Germany
    For correspondence
    marina.mikhaylova@hu-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7646-1346

Funding

Deutsche Forschungsgemeinschaft (MI1923/1-2)

  • Marina Mikhaylova

Deutsche Forschungsgemeinschaft (FOR2419 TP2)

  • Marina Mikhaylova

Deutsche Forschungsgemeinschaft (EXC-2049-390688087)

  • Marina Mikhaylova

Leibniz-Gemeinschaft (Neurotranslation)

  • Michael R Kreutz

Deutscher Akademischer Austauschdienst (Research Stays for University Academics and Scientists Award)

  • Alla S Kostyukova

Hamburg Landesforschungsförderung (LFF-FV76)

  • Marina Mikhaylova

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

Ethics

Animal experimentation: All animal experiments were carried out in accordance with the European Communities Council Directive (2010/63/EU) and the Animal Welfare Law of the Federal Republic of Germany (Tierschutzgesetz der Bundesrepublik Deutschland, TierSchG) approved by the local authorities of the city-state Hamburg (Behörde für Gesundheit und Verbraucherschutz, Fachbereich Veterinärwesen) and the animal care committee of the University Medical Center Hamburg-Eppendorf.

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Publication history

  1. Received: December 30, 2020
  2. Accepted: May 1, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)

Copyright

© 2021, Bucher 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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