ArticleThe Journal of biological chemistry2019
Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Structure and mechanism of the HECT ligase HECTD3.Nature communications · 2026Article
- Predictable Modulation of a Spontaneous Post-translational Modification in Living Cells.Angewandte Chemie (International ed. in English) · 2025Article
- Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1.Nature communications · 2025Article
- Chemical Tools for Probing the Ub/Ubl Conjugation Cascades.Chembiochem : a European journal of chemical biology · 2025Review
- Neuronal UBE3A substrates hold therapeutic potential for Angelman syndrome.Current opinion in neurobiology · 2024Review
- Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing.Nature communications · 2024Article
- Electrostatic and steric effects underlie acetylation-induced changes in ubiquitin structure and function.Nature communications · 2022Article
- Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis.Nature communications · 2021Article
- Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe.ACS chemical biology · 2021Article
- Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation.Molecular cell · 2020Article
- Cryo-EM Reveals Unanchored M1-Ubiquitin Chain Binding at hRpn11 of the 26S Proteasome.Structure (London, England : 1993) · 2020Article
- Crystal structure of the catalytic C-lobe of the HECT-type ubiquitin ligase E6AP.Protein science : a publication of the Protein Society · 2020Article
- Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10.Nature communications · 2020Article
- An Angelman syndrome substitution in the HECT E3 ubiquitin ligase C-terminal Lobe of E6AP affects protein stability and activity.PloS one · 2020Article
- Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly.F1000Research · 2020Review
- Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases.The Journal of biological chemistry · 2019Article
- Enzymatic Logic of Ubiquitin Chain Assembly.Frontiers in physiology · 2019Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
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