System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes
Open accessAbstract
HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.
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HECT ligases bind the target then transfer ubiquitin onto themselves before transferring ubiquitin to the target.
“The second class, HECT ligases, bind the target then use an intermediate strategy of transferring ubiquitin onto themselves before transferring ubiquitin to the target112,113.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [112]
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- Authors
- Zhang, W., Wu, K.-P., Sartori, M. A., Kamadurai, H. B., Ordureau, A., Jiang, C., Mercredi, P. Y., Murchie, R., Hu, J., Persaud, A., Mukherjee, M., Li, N., Doye, A., Walker, J. R., Sheng, Y., Hao, Z., Li, Y., Brown, K. R., Lemichez, E., Chen, J., Tong, Y., Harper, J. W., Moffat, J., Rotin, D., Schulman, B. A., & Sidhu, S. S.
- Affiliations
- University of Toronto (CA)
- St. Jude Children's Research Hospital (US)
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Inserm (FR)
- York University (CA)
- University Health Network (CA)
- Corresponding author
- Schulman, Brenda A.
- Sidhu, Sachdev S.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 62
- Issue
- 1
- Pages
- 121-136
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4988125
- OpenAlex
- W2290268596
- Cited by
- 168
- References
- 63
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 10 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 14 · 2019: 26 · 2018: 16 · 2017: 27 · 2016: 10
- FWCI
- 13.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- NIH (R37NS083524, GM095567, DE-AC02-06CH11357, R37GM065930, P30CA021765, P41 GM103403)
- Edward R. and Anne G. Lefler Center
- CIHR (130422, 111149, 136956)
- ALSAC
- DOE
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (115766)
- Janssen, Merck & Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- São Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- HECT E3 ubiquitin ligase, ubiquitin variants, NEDD4, NEDD4L, E2 binding sites, ubiquitination, cell migration, intestinal organoids, genetic screen, small molecule inhibitors
- MeSH terms
- Animals, Cell Line, Cell Movement, Dogs, Humans, Models, Molecular, Organoids, Peptide Library, Catalytic Domain, Ubiquitin, Ubiquitin-Protein Ligases, HCT116 Cells, Madin Darby Canine Kidney Cells
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