Metal loading capacity of Abeta N-terminus: a combined potentiometric and spectroscopic study of zinc(II) complexes with Abeta(1-16), its short or mutated peptide fragments and its polyethylene glycol-ylated analogue.
Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's Disease (AD). There is now compelling evidence that metal binding to Abeta is involved in AD pathogenesis. The amino acid region 1-16 is widely considered as the metal binding domain of Abeta. In this work, we used a combined potentiometric, NMR, and electrospray ionization mass spectrometry (ESI-MS) approach to study the zinc(II) binding to a new polyethylene glycol (PEG)-conjugated peptide fragment encompassing the 1-16 amino acid sequence of Abeta (Abeta(1-16)PEG). Our results demonstrate for the first time that the Abeta(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(II) complexes of a series of shorter peptide fragments related to the Abeta(1-16) sequence, namely, Abeta(1-4), Abeta(1-6), AcAbeta(1-6), AcAbeta(8-16)Y10A. The comparison of the whole results allowed the identification of the zinc(II) preferred binding sites within the longer Abeta(1-16) amino acid sequence. Unlike copper(II) that prefers the N-terminal amino group as the main binding site, the zinc(II) is preferentially placed in the 8-16 amino acidic region of Abeta(1-16).
Department of Chemical Sciences, University of Catania, V. le A. Doria 6, 95125 Catania, Italy.
Chiara A
CA
Damante
Katalin
K
Osz
Zoltán
Z
Nagy
Giuseppe
G
Pappalardo
Giulia
G
Grasso
Giuseppe
G
Impellizzeri
Enrico
E
Rizzarelli
Imre
I
Sóvágó
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D003300:Copper / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011199:Potentiometry; D013057:Spectrum Analysis; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C433241:amyloid beta-protein (1-16); D011092:Polyethylene Glycols; D003300:Copper; D015032:Zinc