Interference with Amyloid-? Nucleation by Transient Ligand Interaction.

ABSTRACT: Amyloid-? peptide (A?) is an intrinsically disordered protein (IDP) associated with Alzheimer's disease. The structural flexibility and aggregation propensity of A? pose major challenges for elucidating the interaction between A? monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and A?42 monomers, and how the interaction influences A?42 aggregation. We demonstrate for the first time that D3 binds to A?42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the ?-sheet formation and A?42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects A? assemblies and contributes to our knowledge on the interaction between two IDPs.

SUBMITTER: Zhang T 

PROVIDER: S-EPMC6600523 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature