Copper mediated amyloid-β binding to Transthyretin

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Transthyretin (TTR) transports thyroxine and retinol, and protects against Alzheimer's disease (AD) by modulating amyloid-beta (Aβ) deposition.
• Lower TTR levels are observed in the cerebrospinal fluid (CSF) of AD patients.
• Metal ions like Zn2+, Mn2+, and Fe2+ can transform TTR into a protease that cleaves Aβ.

Purpose of the Study:

• To investigate the conformational changes in TTR induced by metal ions, specifically copper (Cu2+) and iron (Fe2+).
• To elucidate the mechanism of TTR's interaction with Aβ, particularly in the presence of Cu2+.
• To understand how metal binding affects TTR's structure and its Aβ-neutralizing capabilities.

Main Methods:

• X-ray crystallography to observe conformational changes in TTR crystals exposed to copper and iron salts.
• Bio-layer interferometry (BLI) to study the binding interaction between TTR and immobilized Aβ(1-28) in the presence of Cu2+.
• Analysis of TTR crystal structures with and without Aβ(1-28) in the presence of copper.

Main Results:

• Exposure to Cu2+ or Fe2+ salts induces significant conformational changes in the TTR tetramer, altering the dimer-dimer interface.
• Cu2+-dependent binding of TTR to Aβ(1-28) was observed, suggesting a recognition mechanism involving Cu2+ modulation of both TTR and Aβ structures.
• Cu2+-soaked TTR crystals exhibit a different conformation compared to Fe2+-induced changes, and copper binding sites differ in TTR crystals grown with Aβ(1-28).

Conclusions:

• Metal ions, particularly Cu2+, play a crucial role in modulating TTR conformation and its interaction with Aβ.
• The Cu2+-mediated interaction suggests a novel mechanism for TTR's role in Aβ modulation, potentially relevant to Alzheimer's disease.
• Understanding these metal-ion-induced structural changes in TTR could lead to new therapeutic strategies for AD.