Structural Insight into Redox Dynamics of Copper Bound N-Truncated Amyloid-β Peptides from in Situ X-ray Absorption...

Area of Science:

• Biophysical Chemistry
• Metalloprotein Chemistry
• Neuroscience

Background:

• Amyloid-β (Aβ) peptides are implicated in neurodegenerative diseases.
• Copper ions interact with Aβ peptides, influencing their aggregation and redox activity.
• Understanding copper binding and redox states in Aβ is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To elucidate the redox properties of Cu(II) bound to truncated amyloid-β peptides using X-ray absorption spectroscopy under electrochemical control (XAS-EC).
• To investigate the influence of specific amino acid residues, particularly the ATCUN motif, on copper binding and reduction.
• To determine the coordination environment and geometry of copper in different oxidation and ligation states.

Main Methods:

• X-ray absorption spectroscopy (XAS) of Cu(II)-amyloid-β peptide complexes.
• In situ electrochemical control (XAS-EC) to study redox properties.
• Low-temperature (10 K) XAS measurements.
• Electron Paramagnetic Resonance (EPR) spectroscopy.

Main Results:

• Identified distinct Cu(II) binding environments in Aβ(1-16) versus N-truncated peptides (Aβ(4-9/12/16)).
• The N-terminal sequence (F4R5H6) forms a high-affinity amino-terminal copper nickel (ATCUN) binding motif.
• Observed a tetragonal pyramid geometry for Cu(II) in Aβ(4-9/12/16) due to ATCUN binding and a water ligand.
• Demonstrated that Cu(II):Aβ(4-16) and Cu(II):Aβ(1-16) reduce at mild potentials, while Aβ(4-9/12) require harsher conditions.
• Showed that His13 and His14 significantly enhance the rate of Cu(II) reduction.
• Characterized the Cu(I) coordination as terdentate (His13, His14, amide oxygen) with a water ligand, forming a quasi-tetrahedral geometry.
• Structural parameters for oxidized Cu(II):Aβ(4-12/16) are consistent with crystallographic data for Cu(III) and Cu(II)ATCUN complexes.

Conclusions:

• The ATCUN motif plays a critical role in defining the copper binding site and redox behavior in truncated Aβ peptides.
• The presence of His13 and His14 residues is essential for facile reduction of Cu(II) at mild potentials.
• Copper ions and their oxidation products appear to be accommodated within ATCUN-like binding sites in Aβ peptides.