ArticleThe Journal of biological chemistry2015
Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 66 citations in OpenAlex.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer.Cell death and differentiation · 2026Article
- HECT ubiquitin ligases as regulators of inflammatory signalling.Cell death and differentiation · 2026Review
- Ndfip2 in TrkA-expressing sensory neurons regulates noxious mechanosensation through control of TrkA signaling and protein levels.Cell death & disease · 2026Article
- ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.Science advances · 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
- Article
- Chemical Tools for Probing the Ub/Ubl Conjugation Cascades.Chembiochem : a European journal of chemical biology · 2025Review
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.EMBO reports · 2024Article
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Cryo-EM structure of the chain-elongating E3 ubiquitin ligase UBR5.The EMBO journal · 2023Article
- Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates.The Journal of biological chemistry · 2022Article
- Research progress of Nedd4L in cardiovascular diseases.Cell death discovery · 2022Review
- ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer.EMBO reports · 2022Article
- The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.International journal of molecular sciences · 2021Review
- Ubiquitin Ligase Activities of WWP1 Germline Variants K740N and N745S.Biochemistry · 2021Article
- Exploration of Aberrant E3 Ligases Implicated in Alzheimer's Disease and Development of Chemical Tools to Modulate Their Function.Frontiers in cellular neuroscience · 2021Review
- WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
Nedd4-family E3 ubiquitin ligases regulate an array of biologic processes. Autoinhibition maintains these catalytic ligases in an inactive state through several mechanisms. However, although some Nedd4 family members are activated by binding to Nedd4 family-interacting proteins (Ndfips), how binding activates E3 function remains unclear. Our data reveal how these two regulatory processes are linked functionally. In the absence of Ndfip1, the Nedd4 family member Itch can bind an E2 but cannot accept ubiquitin onto its catalytic cysteine. This is because Itch is autoinhibited by an intramolecular interaction between its HECT (homologous to the E6-AP carboxy terminus domain) and two central WW domains. Ndfip1 binds these WW domains to release the HECT, allowing trans-thiolation and Itch catalytic activity. This molecular switch also regulates the closely related family member WWP2. Importantly, multiple PY motifs are required for Ndfip1 to activate Itch, functionally distinguishing Ndfips from single PY-containing substrates. These data establish a novel mechanism for control of the function of a subfamily of Nedd4 E3 ligases at the level of E2-E3 trans-thiolation.
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Registered trials
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.