Activation of E6AP/UBE3A-Mediated Protein Ubiquitination and Degradation Pathways by a Cyclic γ-AA Peptide.
J Med Chem
; 65(3): 2497-2506, 2022 02 10.
Article
in En
| MEDLINE
| ID: mdl-35045253
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 substrate proteins UbxD8, HHR23A, and ß-catenin in reconstituted reactions and HEK293T cells. Furthermore, P6 can accelerate the degradation of E6AP substrates in the cell by enhancing the catalytic activities of E6AP. Our work demonstrates the feasibility of using synthetic ligands to stimulate E3 activities in the cell. The E3 stimulators could be developed alongside E3 inhibitors and substrate recruiters such as PROTACs and molecular glues to leverage the full potential of protein ubiquitination pathways for drug development.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides, Cyclic
/
Enzyme Activators
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Ubiquitin-Protein Ligases
/
Ubiquitination
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Peptidomimetics
/
Proteolysis
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2022
Document type:
Article
Affiliation country:
United States