Solution NMR Studies of A? Monomer Dynamics.

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Solution NMR Studies of A? Monomer Dynamics.

Solution NMR Studies of A? Monomer Dynamics.

Protein Pept Lett. 2011 Jan 11;

Authors: Wang C

A? is widely recognized as a key molecule in Alzheimer's disease, causing neurotoxicity through A? aggregates such as A? oligomers and fibrils. A?40 and A?42, composed of 40 and 42 residues, respectively, are the major A? species in human brain. A?42 aggregates much faster than A?40 but the mechanism of such difference in aggregation propensity is poorly understood. Using NMR spin relaxation, we have shown that A?40 and A?42 monomers have different dynamics in both backbone and sidechain on the ps-ns time scale. A?42 is more rigid in C-terminus in both backbone and sidechain while A?40 has more rigid methyl groups in the central hydrophobic cluster (CHC: A?17-21). These observations are consistent with differences in the major conformations of A?40 and A?42 monomers derived from replica exchange MD (REMD). To further demonstrate the relevance of dynamics in aggregation mechanism, a perturbation was introduced to A?42 in the form of M35 oxidation. After M35 side chain oxidation to sulfoxide, A?42 experiences A?40-like changes in dynamics. At the same time, M35 oxidation causes dramatic reduction in A?42 aggregation rate. These data have thus established an important role for protein dynamics in the mechanism of A? aggregation.

PMID: 21222639 [PubMed - as supplied by publisher]



Source: PubMed