Metal Loading Capacity of Aβ N-Terminus: a Combined Potentiometric and Spectroscopic Study of Zinc(ll) Complexes with Aβ(1—16), Its Short or Mutated Peptide Fragments and Its Polyethylene Glycol—ylated Analogue.

Aggregation of the amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer's Disease (Aβ). There is now compelling evidence that metal binding to Aβ is involved in AD pathogenesis. The amino acid region 1-16 is widely considered as the metal binding domain of Aβ. In this work, we used a combined potenliometric, NMR, and electrospray ionization mass speclrometry (ESI-MS) approach to study the zinc(ll) binding to a new polyethylene glycol (PEG)-conjugated peptide fragmenl encompassing the 1-16 amino acid sequence of Aβ (Aβ(1-16)PEG). Our results demonstrate for the first time that the Aβ(1 -16) is able to coordinate up to three zinc ions, all the histidyl residues acting as independent anchor sites. The study was complemented by systematically investigating the zinc(ll) complexes of a series of shorter peplide tragmenls related to the Aβ(1-16) sequence, namely, (1-4), Aβ(1-6), AcAβ(1-6), AcAβ(8-16)Y10A. The comparison of the whole results allowed the identification of the zinc(II) preferred binding sites within the longer Aβ(1-16) amino acid sequence. Unlike copper(ll) that prefers the N-terminal amino group as the main binding site, the zinc(ll) is preferentially placed in the 8-16 amino acidic region of Aβ(1-16). [ABSTRACT FROM AUTHOR]