A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency

  1. Tara L Mastro  Is a corresponding author
  2. Anthony Preza
  3. Shinjini Basu
  4. Sumantra Chattarji
  5. Sally M Till
  6. Peter C Kind
  7. Mary B Kennedy  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of Edinburgh, United Kingdom
  3. National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Abstract

SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of Syngap1 in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young Syngap1+/- mice. Here we show that only females and not males show a highly significant correlation between an increase in TARP and a decrease in synGAP in the PSDs of Syngap1+/- rodents. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP haploinsufficiency.

Data availability

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

Article and author information

Author details

  1. Tara L Mastro

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    tmastro@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Anthony Preza

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shinjini Basu

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Sumantra Chattarji

    National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9962-3635
  5. Sally M Till

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter C Kind

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4256-9639
  7. Mary B Kennedy

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    kennedym@its.caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1369-0525

Funding

National Institute of Mental Health (MH15456)

  • Tara L Mastro
  • Anthony Preza
  • Mary B Kennedy

Allen and Lenabelle Davis Foundation (Professorship)

  • Mary B Kennedy

National Science Foundation (Postdoctoral Fellowship)

  • Tara L Mastro

Department of Biotechnology , Ministry of Science and Technology

  • Sumantra Chattarji
  • Peter C Kind

Simons Foundation (Grant 529085)

  • Peter C Kind

Patrick Wild Centre (Patrick Wild Centre)

  • Sally M Till
  • Peter C Kind

Medical Research Council (MR/P006213/1)

  • Sally M Till
  • Peter C Kind

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (1034-18) of California Institute of Technology.

Copyright

© 2020, Mastro 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.

Metrics

  • 1,786
    views
  • 257
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Tara L Mastro
  2. Anthony Preza
  3. Shinjini Basu
  4. Sumantra Chattarji
  5. Sally M Till
  6. Peter C Kind
  7. Mary B Kennedy
(2020)
A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency
eLife 9:e52656.
https://doi.org/10.7554/eLife.52656

Share this article

https://doi.org/10.7554/eLife.52656

Further reading

    1. Biochemistry and Chemical Biology
    2. Genetics and Genomics
    Federico A Vignale, Andrea Hernandez Garcia ... Adrian G Turjanski
    Research Article

    Yerba mate (YM, Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large YM genome size is partly due to a whole-genome duplication (Ip-α) during the early evolutionary history of Ilex, in addition to the hexaploidization event (γ) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in YM and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the X-ray diffraction data suggest structural constraints are minimal for the convergent evolution of individual reactions.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Angel D'Oliviera, Xuhang Dai ... Jeffrey S Mugridge
    Research Article

    The SARS-CoV-2 main protease (Mpro or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an Mpro-TRMT1 peptide complex that shows how TRMT1 engages the Mpro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 Mpro that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.