Inherent Biophysical Properties Modulate the Toxicity of Soluble Amyloidogenic Light Chains

Martina Maritan, Margherita Romeo, Luca Oberti, Pietro Sormanni, Masayoshi Tasaki, Rosaria Russo, Arianna Ambrosetti, Paolo Motta, Paola Rognoni, Giulia Mazzini, Alberto Barbiroli, Giovanni Palladini, Michele Vendruscolo, Luisa Diomede, Martino Bolognesi, Giampaolo Merlini, Francesca Lavatelli, Stefano Ricagno

Research output: Contribution to journalArticle

Abstract

In light chain amyloidosis (AL), fibrillar deposition of monoclonal immunoglobulin light chains (LCs) in vital organs, such as heart, is associated with their severe dysfunction. In addition to the cellular damage caused by fibril deposition, direct toxicity of soluble prefibrillar amyloidogenic proteins has been reported, in particular, for cardiotoxicity. However, the molecular bases of proteotoxicity by soluble LCs have not been clarified. Here, to address this issue, we rationally engineered the amino acid sequence of the highly cardiotoxic LC H6 by introducing three residue mutations, designed to reduce the dynamics of its native state. The resulting mutant (mH6) is less toxic than its parent H6 to human cardiac fibroblasts and C. elegans. The high sequence and structural similarity, together with the different toxicity, make H6 and its non-toxic designed variant mH6 a test case to shed light on the molecular properties underlying soluble toxicity. Our comparative structural and biochemical study of H6 and mH6 shows closely matching crystal structures, whereas spectroscopic data and limited proteolysis indicate that H6 displays poorly cooperative fold, higher flexibility, and kinetic instability, and a higher dynamic state in its native fold. Taken together, the results of this study show a strong correlation between the overall conformational properties of the native fold and the proteotoxicity of cardiotropic LCs.

Original languageEnglish
JournalJournal of Molecular Biology
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Keywords

  • fold stability
  • light chain amyloidosis
  • protein dynamics
  • protein structure
  • proteotoxicity

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Maritan, M., Romeo, M., Oberti, L., Sormanni, P., Tasaki, M., Russo, R., Ambrosetti, A., Motta, P., Rognoni, P., Mazzini, G., Barbiroli, A., Palladini, G., Vendruscolo, M., Diomede, L., Bolognesi, M., Merlini, G., Lavatelli, F., & Ricagno, S. (Accepted/In press). Inherent Biophysical Properties Modulate the Toxicity of Soluble Amyloidogenic Light Chains. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2019.12.015