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E3 ubiquitin ligase components C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [25]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction.
E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.
E3 ligases are being exploited as pharmacological targets to facilitate targeted protein degradation (TPD), as an alternative to small molecule inhibitors [2], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues.
Enzymes
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Cbl proto-oncogene B Show summary »« Hide summary
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cereblon
C
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DDB1 and CUL4 associated factor 1 Show summary »« Hide summary
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F-box protein 3 Show summary »« Hide summary
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kelch domain containing 2 Show summary »« Hide summary
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kelch like family member 12 Show summary »« Hide summary
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MDM2 proto-oncogene
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S-phase kinase associated protein 2 Show summary »« Hide summary
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STIP1 homology and U-box containing protein 1
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ubiquitin protein ligase E3 component n-recognin 2 Show summary »« Hide summary
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von Hippel-Lindau tumor suppressor Show summary »« Hide summary
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zinc finger and BTB domain containing 25 Show summary »« Hide summary
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Further reading
* Key recommended reading is highlighted with an asterisk
* Asatsuma-Okumura T, Ito T, Handa H. (2019) Molecular mechanisms of cereblon-based drugs. Pharmacol Ther, 202: 132-139. [PMID:31202702]
* Chamberlain PP, Hamann LG. (2019) Development of targeted protein degradation therapeutics. Nat Chem Biol, 15 (10): 937-944. DOI: 10.1038/s41589-019-0362-y [PMID:31527835]
References
1. Augustin RC, Bao R, Luke JJ. (2023) Targeting Cbl-b in cancer immunotherapy. J Immunother Cancer, 11 (2). [PMID:36750253]
2. Belcher BP, Ward CC, Nomura DK. (2023) Ligandability of E3 Ligases for Targeted Protein Degradation Applications. Biochemistry, 62 (3): 588-600. [PMID:34473924]
3. Benita Y, Cao Z, Giallourakis C, Li C, Gardet A, Xavier RJ. (2010) Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. Blood, 115 (26): 5376-84. [PMID:20410506]
4. Cao Z, Li G, Shao Q, Yang G, Zheng L, Zhang T, Zhao Y. (2016) CHIP: A new modulator of human malignant disorders. Oncotarget, 7 (20): 29864-74. [PMID:27007160]
5. Chardin P, Courtois G, Mattei MG, Gisselbrecht S. (1991) The KUP gene, located on human chromosome 14, encodes a protein with two distant zinc fingers. Nucleic Acids Res, 19 (7): 1431-6. [PMID:2027750]
6. Chen B, Mallampalli R. (2018) Compositions and methods for treating respiratory injury or disease. Patent number: US20180071232A. Assignee: University of Pittsburgh , US Department of Veterans Affairs VA. Priority date: 17/11/2017. Publication date: 15/03/2018.
7. Dale B, Anderson C, Park KS, Kaniskan HÜ, Ma A, Shen Y, Zhang C, Xie L, Chen X, Yu X et al.. (2022) Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2. ACS Pharmacol Transl Sci, 5 (7): 491-507. [PMID:35837138]
8. Gao S, Zhang G, Zhang Z, Zhu JZ, Li L, Zhou Y, Rodney Jr GG, Abo-Zahrah RS, Anderson L, Garcia JM et al.. (2022) UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting. Proc Natl Acad Sci U S A, 119 (43): e2200215119. [PMID:36252004]
9. Han S, Liu ZQ, Chung DC, Paul MS, Garcia-Batres CR, Sayad A, Elford AR, Gold MJ, Grimshaw N, Ohashi PS. (2022) Overproduction of IFNγ by Cbl-b-Deficient CD8+ T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity. Cancer Immunol Res, 10 (4): 437-452. [PMID:35181779]
10. Huang ST, Chen DH, Ren T, Thomas N, Wu J, Sankaran B, Jones R, Taylor S, Chen Y. (2025) An alternative pocket for binding the N-degrons by the UBR1 and UBR2 ubiquitin E3 ligases. Protein Sci, 34 (8): e70248. [PMID:40880185]
11. Huang ST, Faouzi A, Thomas N, Wu J, Pestonjamasp K, Chen DH, Ren T, Kuang Y, Taylor S, Chen Y. (2026) Development of High-Affinity Ligands for Human UBR2. J Med Chem, 69 (10): 11738-11751. [PMID:42102356]
12. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. (2010) Identification of a primary target of thalidomide teratogenicity. Science, 327 (5971): 1345-50. [PMID:20223979]
13. Jafari D, Mousavi MJ, Keshavarz Shahbaz S, Jafarzadeh L, Tahmasebi S, Spoor J, Esmaeilzadeh A. (2021) E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy. Clin Exp Immunol, 204 (1): 14-31. [PMID:33306199]
14. Joshi V, Amanullah A, Upadhyay A, Mishra R, Kumar A, Mishra A. (2016) A Decade of Boon or Burden: What Has the CHIP Ever Done for Cellular Protein Quality Control Mechanism Implicated in Neurodegeneration and Aging?. Front Mol Neurosci, 9: 93. [PMID:27757073]
15. Karemaker ID, Vermeulen M. (2018) ZBTB2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation. EMBO Rep, 19 (4). [PMID:29437775]
16. Kim JG, Shin HC, Seo T, Nawale L, Han G, Kim BY, Kim SJ, Cha-Molstad H. (2021) Signaling Pathways Regulated by UBR Box-Containing E3 Ligases. Int J Mol Sci, 22 (15). [PMID:34361089]
17. Kim Y, Seo P, Jeon E, You I, Hwang K, Kim N, Tse J, Bae J, Choi HS, Hinshaw SM et al.. (2023) Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase. Cell Chem Biol, 30 (11): 1414-1420.e5. [PMID:37567174]
18. Koren I, Timms RT, Kula T, Xu Q, Li MZ, Elledge SJ. (2018) The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell, 173 (7): 1622-1635.e14. [PMID:29779948]
19. Kumar S, Basu M, Ghosh MK. (2021) Chaperone-assisted E3 ligase CHIP: A double agent in cancer. Genes & Diseases, Epub ahead of print. DOI: 10.1016/j.gendis.2021.08.003
20. Le LTHL, Park S, Lee JH, Kim YK, Lee MJ. (2024) N-recognins UBR1 and UBR2 as central ER stress sensors in mammals. Mol Cells, 47 (1): 100001. [PMID:38376480]
21. Lear TB, Boudreau ÁN, Lockwood KC, Chu E, Camarco DP, Cao Q, Nguyen M, Evankovich JW, Finkel T, Liu Y et al.. (2023) E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro. J Biol Chem, 299 (12): 105388. [PMID:37890782]
22. Li ASM, Kimani S, Wilson B, Noureldin M, González-Álvarez H, Mamai A, Hoffer L, Guilinger JP, Zhang Y, von Rechenberg M et al.. (2023) Discovery of Nanomolar DCAF1 Small Molecule Ligands. J Med Chem, 66 (7): 5041-5060. [PMID:36948210]
23. Lin HC, Yeh CW, Chen YF, Lee TT, Hsieh PY, Rusnac DV, Lin SY, Elledge SJ, Zheng N, Yen HS. (2018) C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases. Mol Cell, 70 (4): 602-613.e3. [PMID:29775578]
24. Matta-Camacho E, Kozlov G, Li FF, Gehring K. (2010) Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat Struct Mol Biol, 17 (10): 1182-7. [PMID:20835242]
25. Morreale FE, Walden H. (2016) Types of Ubiquitin Ligases. Cell, 165 (1): 248-248.e1. [PMID:27015313]
26. Muñoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K. (2017) Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase. Structure, 25 (5): 719-729.e3. [PMID:28392261]
27. Ng S, Brueckner AC, Bahmanjah S, Deng Q, Johnston JM, Ge L, Duggal R, Habulihaz B, Barlock B, Ha S et al.. (2022) Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1. J Med Chem, [Epub ahead of print]. [PMID:35853179]
28. Oh JH, Hyun JY, Chen SJ, Varshavsky A. (2020) Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling. Proc Natl Acad Sci U S A, 117 (20): 10778-10788. [PMID:32366662]
29. Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR, Tsue AF, Bush MF, Yen HS, Zheng N. (2018) Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase. Mol Cell, 72 (5): 813-822.e4. [PMID:30526872]
30. Sands AT, Bence NF, Zapf CW, Cohen F, Wang C, Cummins T, Tanaka H, Shunatona H, Cardozo M, Weiss D et al.. (2020) Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof. Patent number: WO2020264398A1. Assignee: Nurix Therapeutics, Inc.. Priority date: 26/06/2020. Publication date: 30/12/2020.
31. Tao Y, Remillard D, Vinogradova EV, Yokoyama M, Banchenko S, Schwefel D, Melillo B, Schreiber SL, Zhang X, Cravatt BF. (2022) Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1. J Am Chem Soc, 144 (40): 18688-18699. [PMID:36170674]
32. Villa E, Paul R, Meynet O, Volturo S, Pinna G, Ricci JE. (2020) The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway. Cell Death Dis, 11 (12): 1041. [PMID:33288741]
33. Vu TTM, Mitchell DC, Gygi SP, Varshavsky A. (2020) The Arg/N-degron pathway targets transcription factors and regulates specific genes. Proc Natl Acad Sci U S A, 117 (49): 31094-31104. [PMID:33229537]
34. Vulpetti A, Holzer P, Schmiedeberg N, Imbach-Weese P, Pissot-Soldermann C, Hollingworth GJ, Radimerski T, Thoma CR, Stachyra TM, Wojtynek M et al.. (2023) Discovery of New Binders for DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field. ACS Med Chem Lett, 14 (7): 949-954. [PMID:37465299]
35. Wang J, Yang D, Shen X, Wang J, Liu X, Lin J, Zhong J, Zhao Y, Qi Z. (2020) BPTES inhibits anthrax lethal toxin-induced inflammatory response. Int Immunopharmacol, 85: 106664. [PMID:32521490]
36. Waterson AG, Vadukoot A, Jana S, Cui J, Luong K, Rietz TA, Madrigal-Carrillo EA, Lehmann BD, Sensintaffar JL, Zhao B et al.. (2026) Identification of KLHL12 Ligands Using Fragment-Based Methods. J Med Chem, 69 (7): 7709-7731. [PMID:41906311]
37. Xu H, Shi J, Gao H, Liu Y, Yang Z, Shao F, Dong N. (2019) The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin. EMBO J, 38 (13): e101996. [PMID:31268597]
38. Zhang K, Hu K, Li Q, Li M, Gao K, Yang K, Zhao B, Shi XJ, Zhang L, Liu HM. (2023) Discovery of Novel 1,3-Diphenylpyrazine Derivatives as Potent S-Phase Kinase-Associated Protein 2 (Skp2) Inhibitors for the Treatment of Cancer. J Med Chem, 66 (11): 7221-7242. [PMID:37204466]
NC-IUPHAR subcommittee and family contributors
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Elena Faccenda
Robert Layfield |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Enzymes. Br J Pharmacol. 182: S307-S403.
