Effect of zinc binding on ?-amyloid structure and dynamics: implications for A? aggregation.

ABSTRACT: Assembly of ?-amyloid (A?) peptide into toxic oligomers is widely believed to initiate Alzheimer's disease pathogenesis. Under in vitro physiological conditions, zinc (Zn(II)) can bind to A? and redirect its assembly from amyloid fibrillar toward less toxic amorphous aggregation. Propensity of A? 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 A?40 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 A?42, the more fibrillar aggregation-prone variant of A?. The combined data suggest that, upon Zn(II)-binding to the N-terminus of A?40, 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 A?42 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.

SUBMITTER: Rezaei-Ghaleh N 

PROVIDER: S-EPMC3164126 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other