title: An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly.
abstract: Amyloid-β (Aβ) self-assembly into cross-β 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. Aβ fibrils feature a sheet-turn-sheet motif in the constituent β-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 β-hairpin mimetic to study the role turn nucleation plays on Aβ self-assembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of Aβ42 to elicit temporal control over Aβ42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if β-hairpin formation occurs during Aβ self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP Aβ42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type Aβ42. Conversely, the cis-AMPP Aβ42 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 Aβ turn conformation provides significant insight into Aβ self-assembly. Specifically, Aβ mutants that adopt stable β-turns form aggregate structures that are unable to enter folding pathways leading to cross-β fibrils and cytotoxic prefibrillar intermediates.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Doran
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Anderson
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Latchney
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Opanashuk
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Nilsson
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D055668:Photochemical Processes / Q000187:drug effects; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D001391:Azo Compounds; D010446:Peptide Fragments; D017319:Photosensitizing Agents; C075222:amyloid beta-protein (1-42); C009850:azobenzene