ArticleNature communications2019
A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 38 citations in OpenAlex.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Identification and validation of an interaction between the E3 ubiquitin ligase WWP1 and the Transcriptional Co-Activator WBP2 in the human heart.Biology open · 2026Article
- HECT ubiquitin ligases as regulators of inflammatory signalling.Cell death and differentiation · 2026Review
- WWP1 gain-of-function drives developmental anoikis through TGFβ pathway during neurodevelopment.Cell death discovery · 2026Article
- WWP2-induced inhibition of hepatocellular carcinoma cellular senescence via the ubiquitination and degradation of p21.Cell death & disease · 2025Article
- Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.Nature communications · 2025Article
- Hepatitis C virus NS3/4A protease cleaves SPG20, a key regulator of lipid droplet turnover, to promote lipid droplet formation.Journal of virology · 2025Article
- Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins.Nature communications · 2025Article
- Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stressiScience · 2025Article
- 3,3'-Diindolylmethane (DIM): A Molecular Scaffold for Inhibition of WWP1 and WWP2, Members of the NEDD4 Family HECT E3 Ligases.ACS omega · 2025Article
- Cardiotoxicity of Chemotherapy: A Multi-OMIC Perspective.Journal of xenobiotics · 2025Review
- Role and therapeutic potential of the NEDD4 family in breast cancer.Frontiers in pharmacology · 2025Review
- Emerging roles for E3 ubiquitin ligases in neural development and disease.Frontiers in cell and developmental biology · 2025Review
- Atypical Hippo signaling network: uncovering novel insights into head and neck cancer biology and advancements in precision intervention.Frontiers in cell and developmental biology · 2025Review
- Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- The role of WWP1 and WWP2 in bone/cartilage development and diseases.Molecular and cellular biochemistry · 2024Review
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Article
- Multiple E3 ligases act as antiviral factors against SARS-CoV-2 via inducing the ubiquitination and degradation of ORF9b.Journal of virology · 2024Article
- Small molecule induced STING degradation facilitated by the HECT ligase HERC4.Nature communications · 2024Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.