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Article Dans Une Revue Scientific Reports Année : 2018

Copper mediated amyloid-β binding to Transthyretin

Lidia Ciccone
Gilles Mourier
  • Fonction : Auteur
Martin Savko
  • Fonction : Auteur
Susanna Nencetti
  • Fonction : Auteur
Elisabetta Orlandini
  • Fonction : Auteur
Denis Servent
  • Fonction : Auteur
Enrico Stura
  • Fonction : Auteur
William Shepard
  • Fonction : Auteur

Résumé

Abstract Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer’s disease (AD), modulates amyloid- β (A β ) deposition by direct interaction and co-localizes with A β in plaques. TTR levels are lower in the CSF of AD patients. Zn 2+ , Mn 2+ and Fe 2+ transform TTR into a protease able to cleave A β . To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR’s ability to neutralize A β . We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized A β (1–28), we observe the binding of TTR only in the presence of copper. Such Cu 2+ -dependent binding suggests a recognition mechanism whereby Cu 2+ modulates both the TTR conformation, induces a complementary A β structure and may participate in the interaction. Cu 2+ -soaked TTR crystals show a conformation different from that induced by Fe 2+ , and intriguingly, TTR crystals grown in presence of A β (1–28) show different positions for the copper sites from those grown its absence.

Dates et versions

hal-04456196 , version 1 (13-02-2024)

Identifiants

Citer

Lidia Ciccone, Carole Fruchart-Gaillard, Gilles Mourier, Martin Savko, Susanna Nencetti, et al.. Copper mediated amyloid-β binding to Transthyretin. Scientific Reports, 2018, 8 (1), pp.13744. ⟨10.1038/s41598-018-31808-5⟩. ⟨hal-04456196⟩
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