Activation of E6AP/UBE3A-Mediated Protein Ubiquitination and Degradation Pathways by a Cyclic γ-AA Peptide.

ABSTRACT: Manipulating the activities of E3 ubiquitin ligases with chemical ligands holds promise for correcting E3 malfunctions and repurposing the E3s for induced protein degradation in the cell. Herein, we report an alternative strategy to proteolysis-targeting chimeras (PROTACs) and molecular glues to induce protein degradation by constructing and screening a γ-AA peptide library for cyclic peptidomimetics binding to the HECT domain of E6AP, an E3 ubiquitinating p53 coerced by the human papillomavirus and regulating pathways implicated in neurodevelopmental disorders such as Angelman syndrome. We found that a γ-AA peptide P6, discovered from the affinity-based screening with the E6AP HECT domain, can significantly stimulate the ubiquitin ligase activity of E6AP to ubiquitinate its substra

SUBMITTER: Huang B 

PROVIDER: S-EPMC8889547 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature