Copper mediated amyloid-β binding to Transthyretin

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 (Aβ) deposition by direct interaction and co-localizes with Aβ in plaques. TTR levels are lower in the CSF of AD patients. Zn2+, Mn2+ and Fe2+ transform TTR into a protease able to cleave Aβ. 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 Aβ. We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized Aβ(1–28), we observe the binding of TTR only in the presence of copper. Such Cu2+-dependent binding suggests a recognition mechanism whereby Cu2+ modulates both the TTR conformation, induces a complementary Aβ structure and may participate in the interaction. Cu2+-soaked TTR crystals show a conformation different from that induced by Fe2+, and intriguingly, TTR crystals grown in presence of Aβ(1–28) show different positions for the copper sites from those grown its absence.

Physiological Metals Can Induce Conformational Changes in Transthyretin Structure: Neuroprotection or Misfolding Induction?

“…The X-ray crystal structure analysis of TTR in complex with Mn 2+ did not show any significant structural differences. Two possible Mn 2+ binding sites were detected around Asp99 and Glu66 in monomer A, and two, Glu66 and Asn98, in monomer B, Figure 4b [52]. In contrast, when wt-TTR crystals were treated with Cu 2+ , these displayed a similar behavior of those soaked with Fe 2+ (Figure 4a) and Re 2+ [31,52].…”

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

“…In 2018, it has been hypothesized that the TTR-Aβ interaction was modulated by metal ions. Different experiments were performed using bio-layer interferometry (BLI) between TTR and the biotinylated peptide Aβ (1-28) with various CuCl 2 concentration (0-12.5 mM) and the results showed that the affinity of TTR for Aβ (1-28) is modulated by copper [138]. Moreover, the crystal structures of TTR obtained in presence of Cu 2+ and Fe 2+ showed a conformational change comparable to that found for the TTR-rhenium complex in which the distances between L110 and L110' increased up to 8.5 Å in one T4-BP, while decreased in the other probably due to the rhenium binding [139].…”

Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer’s Disease

“…While the main component is Aβ, up to 488 other proteins that also influence the process of aggregation have been detected [ 6 ]. For example, a cross-reaction with apolipoprotein A1, cystatin C, or transthyretin inhibits amyloid formation [ 7 , 8 , 9 , 10 , 11 , 12 ]. However, the formation of pathogenic Aβ peptides can be avoided through the cleavage of APP by α-secretase and the release of soluble APPα (sAPPα) (a process referred to as the non-amyloidogenic pathway; Figure 1 ) [ 13 ].…”