1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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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
Research Article
  • Cited 22
  • Views 1,885
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Cite this article as: eLife 2015;4:e10935 doi: 10.7554/eLife.10935

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.

Reviewing Editor

  1. Jeffery W Kelly, Scripps Research Institute, United States

Publication history

  1. Received: August 18, 2015
  2. Accepted: November 17, 2015
  3. Accepted Manuscript published: November 18, 2015 (version 1)
  4. Version of Record published: February 5, 2016 (version 2)

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.

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