An azobenzene photoswitch sheds light on turn nucleation in amyloid-? self-assembly.

ABSTRACT: Amyloid-? (A?) self-assembly into cross-? amyloid fibrils is implicated in a causative role in Alzheimer's disease pathology. Uncertainties persist regarding the mechanisms of amyloid self-assembly and the role of metastable prefibrillar aggregates. A? fibrils feature a sheet-turn-sheet motif in the constituent ?-strands; as such, turn nucleation has been proposed as a rate-limiting step in the self-assembly pathway. Herein, we report the use of an azobenzene ?-hairpin mimetic to study the role turn nucleation plays on A? self-assembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of A?42 to elicit temporal control over A?42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if ?-hairpin formation occurs during A? self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP A?42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type A?42. Conversely, the cis-AMPP A?42 congeners formed nonfibrillar, amorphous aggregates that exhibited no cytotoxicity. Additionally, cis-trans photoisomerization resulted in rapid formation of native-like amyloid fibrils and trans-cis conversion in the fibril state reduced the population of native-like fibrils. Thus, temporal photocontrol over A? turn conformation provides significant insight into A? self-assembly. Specifically, A? mutants that adopt stable ?-turns form aggregate structures that are unable to enter folding pathways leading to cross-? fibrils and cytotoxic prefibrillar intermediates.

SUBMITTER: Doran TM 

PROVIDER: S-EPMC3369795 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other