Mechanism of amyloid ?-protein dimerization determined using single-molecule AFM force spectroscopy.

ABSTRACT: A?42 and A?40 are the two primary alloforms of human amyloid ?-protein (A?). The two additional C-terminal residues of A?42 result in elevated neurotoxicity compared with A?40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for A?42 and A?40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of A?42 and A?40 monomers within dimers. Although the sequence difference between the two peptides is at the C-termini, the N-terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding as N-terminal was considered as disordered segment with no effect on the A? peptide aggregation. These novel properties of A? proteins suggests that the stabilization of N-terminal interactions is a switch in redirecting of amyloids form the neurotoxic aggregation pathway, opening a novel avenue for the disease preventions and treatments.

SUBMITTER: Lv Z 

PROVIDER: S-EPMC3791449 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature