Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction.

ABSTRACT: The transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer's disease is cut processively by γ-secretase through endoproteolysis and tricarboxypeptidase "trimming". We recently developed a prototype substrate TMD mimetic for structural analysis-composed of a helical peptide inhibitor linked to a transition-state analogue-that simultaneously engages a substrate exosite and the active site and is pre-organized to trap the carboxypeptidase transition state. Here, we developed variants of this prototype designed to allow visualization of transition states for endoproteolysis, TMD helix unwinding, and lateral gating of the substrate, identifying potent inhibitors for each class. These TMD mimetics exhibited non-competitive inhibition and occupy both the exosite and the active s

SUBMITTER: Bhattarai S 

PROVIDER: S-EPMC8918029 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature