C-terminal tetrapeptides inhibit A?42-induced neurotoxicity primarily through specific interaction at the N-terminus of A?42.

ABSTRACT: Inhibition of amyloid ?-protein (A?)-induced toxicity is a promising therapeutic strategy for Alzheimer's disease (AD). Previously, we reported that the C-terminal tetrapeptide A?(39-42) is a potent inhibitor of neurotoxicity caused by A?42, the form of A? most closely associated with AD. Here, initial structure-activity relationship studies identified key structural requirements, including chirality, side-chain structure, and a free N-terminus, which control A?(39-42) inhibitory activity. To elucidate the binding site(s) of A?(39-42) on A?42, we used intrinsic tyrosine (Y) fluorescence and solution-state NMR. The data suggest that A?(39-42) binds at several sites, of which the predominant one is located in the N-terminus of A?42, in agreement with recent modeling predictions. Thus, despite the small size of A?(39-42) and the hydrophobic, aliphatic nature of all four side-chains, the interaction of A?(39-42) with A?42 is controlled by specific intermolecular contacts requiring a combination of hydrophobic and electrostatic interactions and a particular stereochemistry.

SUBMITTER: Li H 

PROVIDER: S-EPMC3240737 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature