1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau

  1. Sarah L Griner  Is a corresponding author
  2. Paul Seidler
  3. Jeannette Bowler
  4. Kevin A Murray
  5. Tianxiao Peter Yang
  6. Shruti Sahay
  7. Michael R Sawaya
  8. Duilio Cascio
  9. Jose A Rodriguez
  10. Stephan Philipp
  11. Justyna Sosna
  12. Charles G Glabe
  13. Tamir Gonen
  14. David S Eisenberg  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Los Angeles, United States
  2. University of California, Irvine, United States
  3. Janelia Research Campus, Howard Hughes Medical Institute, United States
https://doi.org/10.7554/eLife.46924
Share this article
Cite this article
  1. Sarah L Griner
  2. Paul Seidler
  3. Jeannette Bowler
  4. Kevin A Murray
  5. Tianxiao Peter Yang
  6. Shruti Sahay
  7. Michael R Sawaya
  8. Duilio Cascio
  9. Jose A Rodriguez
  10. Stephan Philipp
  11. Justyna Sosna
  12. Charles G Glabe
  13. Tamir Gonen
  14. David S Eisenberg
(2019)
Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau
eLife 8:e46924.
https://doi.org/10.7554/eLife.46924
  2. Download BibTeX
  3. Download .RIS

Abstract

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.

Data availability

Diffraction data have been deposited in PDB under the accession code 6O4JSource Data for Toxicity and Seeding data are provided (Figures 2-7)

The following data sets were generated

Article and author information

Author details

  1. Sarah L Griner

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    sgriner@ucla.edu
    Competing interests
    No competing interests declared.

  2. Paul Seidler

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  3. Jeannette Bowler

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  4. Kevin A Murray

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  5. Tianxiao Peter Yang

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4479-5154

  6. Shruti Sahay

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  7. Michael R Sawaya

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  8. Duilio Cascio

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  9. Jose A Rodriguez

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  10. Stephan Philipp

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  11. Justyna Sosna

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  12. Charles G Glabe

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  13. Tamir Gonen

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9254-4069

  14. David S Eisenberg

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    david@mbi.ucla.edu
    Competing interests
    David S Eisenberg, is a SAB member and equity holder in ADRx, Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2432-5419

Funding

National Institutes of Health (R01 AG029430)

  • Sarah L Griner
  • Paul Seidler
  • Jeannette Bowler
  • Kevin A Murray
  • Tianxiao Peter Yang
  • Shruti Sahay
  • Michael R Sawaya
  • Duilio Cascio
  • Jose A Rodriguez
  • David S Eisenberg

Howard Hughes Medical Institute

  • Sarah L Griner
  • Paul Seidler
  • Jeannette Bowler
  • Kevin A Murray
  • Tianxiao Peter Yang
  • Shruti Sahay
  • Michael R Sawaya
  • Duilio Cascio
  • Jose A Rodriguez
  • Tamir Gonen
  • David S Eisenberg

Cure Alzheimer's Fund

  • Stephan Philipp
  • Justyna Sosna
  • Charles G Glabe

National Institutes of Health (R56 AG061847)

  • Paul Seidler

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

Copyright

© 2019, Griner 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

  • 5,863
    views
  • 1,024
    downloads
  • 91
    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. Sarah L Griner
  2. Paul Seidler
  3. Jeannette Bowler
  4. Kevin A Murray
  5. Tianxiao Peter Yang
  6. Shruti Sahay
  7. Michael R Sawaya
  8. Duilio Cascio
  9. Jose A Rodriguez
  10. Stephan Philipp
  11. Justyna Sosna
  12. Charles G Glabe
  13. Tamir Gonen
  14. David S Eisenberg
(2019)
Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau
eLife 8:e46924.
https://doi.org/10.7554/eLife.46924

Share this article

https://doi.org/10.7554/eLife.46924

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Genetics and Genomics

    Yerba mate (Ilex paraguariensis) genome provides new insights into convergent evolution of caffeine biosynthesis

    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

    Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease

    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.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    The nanoscale organization of the Nipah virus fusion protein informs new membrane fusion mechanisms

    Qian Wang, Jinxin Liu ... Qian Liu
    Research Article

    Paramyxovirus membrane fusion requires an attachment protein for receptor binding and a fusion protein for membrane fusion triggering. Nipah virus (NiV) attachment protein (G) binds to ephrinB2 or -B3 receptors, and fusion protein (F) mediates membrane fusion. NiV-F is a class I fusion protein and is activated by endosomal cleavage. The crystal structure of a soluble GCN4-decorated NiV-F shows a hexamer-of-trimer assembly. Here, we used single-molecule localization microscopy to quantify the NiV-F distribution and organization on cell and virus-like particle membranes at a nanometer precision. We found that NiV-F on biological membranes forms distinctive clusters that are independent of endosomal cleavage or expression levels. The sequestration of NiV-F into dense clusters favors membrane fusion triggering. The nano-distribution and organization of NiV-F are susceptible to mutations at the hexamer-of-trimer interface, and the putative oligomerization motif on the transmembrane domain. We also show that NiV-F nanoclusters are maintained by NiV-F–AP-2 interactions and the clathrin coat assembly. We propose that the organization of NiV-F into nanoclusters facilitates membrane fusion triggering by a mixed population of NiV-F molecules with varied degrees of cleavage and opportunities for interacting with the NiV-G/receptor complex. These observations provide insights into the in situ organization and activation mechanisms of the NiV fusion machinery.