title: Effect of zinc binding on β-amyloid structure and dynamics: implications for Aβ aggregation.
abstract: Assembly of β-amyloid (Aβ) peptide into toxic oligomers is widely believed to initiate Alzheimer's disease pathogenesis. Under in vitro physiological conditions, zinc (Zn(II)) can bind to Aβ and redirect its assembly from amyloid fibrillar toward less toxic amorphous aggregation. Propensity of Aβ to go toward a specific form of aggregate state is determined by structural and dynamical properties of the initial monomeric as well as the aggregate state. Here we probe the structural and dynamical impact of binding of Zn(II) to monomeric Aβ40 using NMR spectroscopy. To obtain further support for the importance of intrinsic dynamics in the aggregation precursor, (15)N relaxation measurements were also performed for Aβ42, the more fibrillar aggregation-prone variant of Aβ. The combined data suggest that, upon Zn(II)-binding to the N-terminus of Aβ40, a relatively rigid turnlike structure is induced at residues Val(24)-Lys(28) whereas the residues flanking this region become more mobile on the picosecond-to-nanosecond timescale. This is in contrast to the increased rigidity of Aβ42 at the C-terminus, and proposed to be linked to the higher propensity of Zn(II)-bound peptide to form amorphous aggregates with less entropic penalties than their fibrillar counterparts.
authors: Department for NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany. nare@nmr.mpibpc.mpg.de
authors: Nasrollah
authors: N
authors: Rezaei-Ghaleh
authors: Karin
authors: K
authors: Giller
authors: Stefan
authors: S
authors: Becker
authors: Markus
authors: M
authors: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary / Q000187:drug effects; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D015032:Zinc