Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains

Rosaria Russo, Margherita Romeo, Tim Schulte, Martina Maritan, Luca Oberti, Maria Monica Barzago, Alberto Barbiroli, Carlo Pappone, Luigi Anastasia, Giovanni Palladini, Luisa Diomede, Stefano Ricagno

Research output: Contribution to journalArticlepeer-review

Abstract

Light chain amyloidosis (AL) is caused by the aberrant overproduction of immunoglobulin light chains (LCs). The resulting abnormally high LC concentrations in blood lead to deposit formation in the heart and other target organs. Organ damage is caused not only by the accumulation of bulky amyloid deposits, but extensive clinical data indicate that circulating soluble LCs also exert cardiotoxic effects. The nematode C. elegans has been validated to recapitulate LC soluble toxicity in vivo, and in such a model a role for copper ions in increasing LC soluble toxicity has been reported. Here, we applied microscale thermophoresis, isothermal calorimetry and thermal melting to demonstrate the specific binding of Cu2+ to the variable domain of amyloidogenic H7 with a sub-micromolar affinity. Histidine residues present in the LC sequence are not involved in the binding, and yet their mutation to Ala reduces the soluble toxicity of H7. Copper ions bind to and destabilize the variable domains and induce a limited stabilization in this domain. In summary, the data reported here, elucidate the biochemical bases of the Cu2+-induced toxicity; moreover, they also show that copper binding is just one of the several biochemical traits contributing to LC soluble in vivo toxicity.

Original languageEnglish
Article number950
JournalInternational Journal of Molecular Sciences
Volume23
Issue number2
DOIs
Publication statusPublished - Jan 1 2022

Keywords

  • Copper binding
  • Copper ions
  • Light chain amyloidosis
  • Protein aggregation
  • Soluble toxicity

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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