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

Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

  1. Boris Brumshtein
  2. Shannon R Esswein
  3. Lukasz Salwinski
  4. Martin L Phillips
  5. Alan T Ly
  6. Duilio Cascio
  7. Michael R Sawaya
  8. David S Eisenberg  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Los Angeles, United States
  2. University of California, Los Angeles, United States
https://doi.org/10.7554/eLife.10935
Share this article
Cite this article
  1. Boris Brumshtein
  2. Shannon R Esswein
  3. Lukasz Salwinski
  4. Martin L Phillips
  5. Alan T Ly
  6. Duilio Cascio
  7. Michael R Sawaya
  8. David S Eisenberg
(2015)
Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain
eLife 4:e10935.
https://doi.org/10.7554/eLife.10935
  2. Download BibTeX
  3. Download .RIS

Abstract

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer.

Article and author information

Author details

  1. Boris Brumshtein

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Shannon R Esswein

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Lukasz Salwinski

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Martin L Phillips

    Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Alan T Ly

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Duilio Cascio

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Michael R Sawaya

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. David S Eisenberg

    Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    david@mbi.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Brumshtein 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

  • 2,413
    views
  • 584
    downloads
  • 53
    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. Boris Brumshtein
  2. Shannon R Esswein
  3. Lukasz Salwinski
  4. Martin L Phillips
  5. Alan T Ly
  6. Duilio Cascio
  7. Michael R Sawaya
  8. David S Eisenberg
(2015)
Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain
eLife 4:e10935.
https://doi.org/10.7554/eLife.10935

Share this article

https://doi.org/10.7554/eLife.10935

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth

    Flavie Coquel, Sing-Zong Ho ... Philippe Pasero
    Research Article

    Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.

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

    MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration

    Ana Patrícia Graça, Vadim Nikitushkin ... Gerald Lackner
    Research Article

    Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria. While the biosynthesis of mycofactocin is well established, the gene mftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments in Mycolicibacterium smegmatis demonstrated a growth defect of the ∆mftG mutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    eIF3 engages with 3’-UTR termini of highly translated mRNAs

    Santi Mestre-Fos, Lucas Ferguson ... Jamie HD Cate
    Research Article

    Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.