Biology:Ubiquitin ligase

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Ubiquitin ligase
Identifiers
SymbolUbiquitin ligase
OPM superfamily471
OPM protein4v6p
Membranome240

A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another protein (the substrate) by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein.[1] E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins.[2] The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.[3] Certain E3 ligases have been utilized in targeted protein degradation applications.[4]

Ubiquitination system

Schematic diagram of the ubiquitylation system.

The ubiquitylation reaction proceeds in three or four steps depending on the mechanism of action of the E3 ubiquitin ligase. In the conserved first step, an E1 cysteine residue attacks the ATP-activated C-terminal glycine on ubiquitin, resulting in a thioester Ub-S-E1 complex. The energy from ATP and diphosphate hydrolysis drives the formation of this reactive thioester, and subsequent steps are thermoneutral. Next, a transthiolation reaction occurs, in which an E2 cysteine residue attacks and replaces the E1. HECT domain type E3 ligases will have one more transthiolation reaction to transfer the ubiquitin molecule onto the E3, whereas the much more common RING finger domain type ligases transfer ubiquitin directly from E2 to the substrate.[5] The final step in the first ubiquitylation event is an attack from the target protein lysine amine group, which will remove the cysteine, and form a stable isopeptide bond.[6] One notable exception to this is p21 protein, which appears to be ubiquitylated using its N-terminal amine, thus forming a peptide bond with ubiquitin.[7]

Ubiquitin ligase families

Humans have an estimated 500-1000 E3 ligases, which impart substrate specificity onto the E1 and E2.[8] The E3 ligases are classified into four families: HECT, RING-finger, U-box, and PHD-finger.[8] The RING-finger E3 ligases are the largest family and contain ligases such as the anaphase-promoting complex (APC) and the SCF complex (Skp1-Cullin-F-box protein complex). SCF complexes consist of four proteins: Rbx1, Cul1, Skp1, which are invariant among SCF complexes, and an F-box protein, which varies. Around 70 human F-box proteins have been identified.[9] F-box proteins contain an F-box, which binds the rest of the SCF complex, and a substrate binding domain, which gives the E3 its substrate specificity.[8]

Mono- and poly-ubiquitylation

Ubiquitin with lysine residues (red), N-terminal methionine (blue), and C-terminal glycine (yellow).[10]

Ubiquitin signaling relies on the diversity of ubiquitin tags for the specificity of its message. A protein can be tagged with a single ubiquitin molecule (monoubiquitylation), or variety of different chains of ubiquitin molecules (polyubiquitylation).[11] E3 ubiquitin ligases catalyze polyubiquitination events much in the same way as the single ubiquitylation mechanism, using instead a lysine residue from a ubiquitin molecule currently attached to substrate protein to attack the C-terminus of a new ubiquitin molecule.[6][11] For example, a common 4-ubiquitin tag, linked through the lysine at position 48 (K48) recruits the tagged protein to the proteasome, and subsequent degradation.[11] However, all seven of the ubiquitin lysine residues (K6, K11, K27, K29, K33, K48, and K63), as well as the N-terminal methionine are used in chains in vivo.[11]

Monoubiquitination has been linked to membrane protein endocytosis pathways. For example, phosphorylation of the Tyrosine at position 1045 in the Epidermal Growth Factor Receptor (EGFR) can recruit the RING type E3 ligase c-Cbl, via an SH2 domain. C-Cbl monoubiquitylates EGFR, signaling for its internalization and trafficking to the lysosome.[12]

Monoubiquitination also can regulate cytosolic protein localization. For example, the E3 ligase MDM2 ubiquitylates p53 either for degradation (K48 polyubiquitin chain), or for nuclear export (monoubiquitylation). These events occur in a concentration dependent fashion, suggesting that modulating E3 ligase concentration is a cellular regulatory strategy for controlling protein homeostasis and localization.[13]

Substrate recognition

Ubiquitin ligases are the final, and potentially the most important determinant of substrate specificity in ubiquitination of proteins.[14] The ligases must simultaneously distinguish their protein substrate from thousands of other proteins in the cell, and from other (ubiquitination-inactive) forms of the same protein. This can be achieved by different mechanisms, most of which involve recognition of degrons: specific short amino acid sequences or chemical motifs on the substrate.[15]

N-degrons

Proteolytic cleavage can lead to exposure of residues at the N-terminus of a protein. According to the N-end rule, different N-terminal amino acids (or N-degrons) are recognized to a different extent by their appropriate ubiquitin ligase (N-recognin), influencing the half-life of the protein.[16] For instance, positively charged (Arg, Lys, His) and bulky hydrophobic amino acids (Phe, Trp, Tyr, Leu, Ile) are recognized preferentially and thus considered destabilizing degrons since they allow faster degradation of their proteins.[17]

Phosphodegrons

A phosphorylated degron (green) is stabilized by hydrogen bonding (yellow) between oxygen atoms of its phosphate (red) and side chains of the SCFFBW7ubiquitin ligase (blue). The relevant part of the ubiquitin ligase is shown in gray. PDB entry 2ovr[18]

A degron can be converted into its active form by a post-translational modification[19] such as phosphorylation of a tyrosine, serine or threonine residue.[20] In this case, the ubiquitin ligase exclusively recognizes the phosphorylated version of the substrate due to stabilization within the binding site. For example, FBW7, the F-box substrate recognition unit of an SCFFBW7ubiquitin ligase, stabilizes a phosphorylated substrate by hydrogen binding its arginine residues to the phosphate, as shown in the figure to the right. In absence of the phosphate, residues of FBW7 repel the substrate.[18]

Oxygen and small molecule dependent degrons

The presence of oxygen or other small molecules can influence degron recognition.[18] The von Hippel-Lindau (VHL) protein (substrate recognition part of a specific E3 ligase), for instance, recognizes the hypoxia-inducible factor alpha (HIF-α) only under normal oxygen conditions, when its proline is hydroxylated. Under hypoxia, on the other hand, HIF-a is not hydroxylated, evades ubiquitination and thus operates in the cell at higher concentrations which can initiate transcriptional response to hypoxia.[21] Another example of small molecule control of protein degradation is phytohormone auxin in plants.[22] Auxin binds to TIR1 (the substrate recognition domain of SCFTIR1ubiquitin ligase) increasing the affinity of TIR1 for its substrates (transcriptional repressors: Aux/IAA), and promoting their degradation.

Misfolded and sugar degrons

In addition to recognizing amino acids, ubiquitin ligases can also detect unusual features on substrates that serve as signals for their destruction.[14] For example, San1 (Sir antagonist 1), a nuclear protein quality control in yeast, has a disordered substrate binding domain, which allows it to bind to hydrophobic domains of misfolded proteins.[14] Misfolded or excess unassembled glycoproteins of the ERAD pathway, on the other hand, are recognized by Fbs1 and Fbs2, mammalian F-box proteins of E3 ligases SCFFbs1and SCFFbs2.[23] These recognition domains have small hydrophobic pockets allowing them to bind high-mannose containing glycans.

Structural motifs

In addition to linear degrons, the E3 ligase can in some cases also recognize structural motifs on the substrate.[14] In this case, the 3D motif can allow the substrate to directly relate its biochemical function to ubiquitination. This relation can be demonstrated with TRF1 protein (regulator of human telomere length), which is recognized by its corresponding E3 ligase (FBXO4) via an intermolecular beta sheet interaction. TRF1 cannot be ubiquinated while telomere bound, likely because the same TRF1 domain that binds to its E3 ligase also binds to telomeres.[14]

Disease relevance

E3 ubiquitin ligases regulate homeostasis, cell cycle, and DNA repair pathways, and as a result, a number of these proteins are involved in a variety of cancers, including famously MDM2, BRCA1, and Von Hippel-Lindau tumor suppressor.[24] For example, a mutation of MDM2 has been found in stomach cancer,[25] renal cell carcinoma,[26] and liver cancer[27] (amongst others) to deregulate MDM2 concentrations by increasing its promoter's affinity for the Sp1 transcription factor, causing increased transcription of MDM2 mRNA.[25] Several proteomics-based experimental techniques are available for identifying E3 ubiquitin ligase-substrate pairs,[28] such as proximity-dependent biotin identification (BioID), ubiquitin ligase-substrate trapping, and tandem ubiquitin-binding entities (TUBEs).

Examples

  • A RING (Really Interesting New Gene) domain binds the E2 conjugase and might be found to mediate enzymatic activity in the E2-E3 complex[29]
  • An F-box domain (as in the SCF complex) binds the ubiquitinated substrate. (e.g., Cdc 4, which binds the target protein Sic1; Grr1, which binds Cln).[30]
  • A HECT domain, which is involved in the transfer of ubiquitin from the E2 to the substrate.

Targeted protein degradation

In 2001, work from the labs of Craig Crews and Raymond Deshaies described the development of proteolysis-targeting chimeras (PROTACs).[31] Using a small molecule to recruit an E3 ubiquitin ligase to a target protein, this work demonstrated that induced proximity could be used to effect the ubiquitination and proteasomal degradation of a target protein. PROTACs have been frequently applied using the E3 ubiquitin ligases CRBN[32][33] and VHL[34][35] to degrade various targets of biological and therapeutic relevance. Multiple groups have sought out additional E3 ligases to co-opt for targeted protein degradation such as FBXO22[36][37][38] and KLHDC2.[39]

While PROTACs generally are heterobifunctional compounds linking an E3 ligase binder to a target protein binder, molecular glues also exist that induce protein-protein interactions with E3 ligases, leading to degradation of various substrate proteins. Molecular glues often have been discovered through serendipity,[40][41][42] though various methodologies have been explored to expedite the discovery of molecular glues.[43][44][45][46][47][48]

Biologic modalities for targeted protein degradation have also been explored by fusing E3 ligases to target recognition domains such as nanobodies. These modalities are sometimes referred to as bioPROTACs.[49][50] While bioPROTACs are advantageous for targeting proteins lacking small molecule ligands, challenges in delivery, pharmacokinetics, and immunogenicity have so far precluded clinical development.[51] Studies exploring different delivery mechanisms have sought to address these shortcomings.[52] In another variant of this idea, bispecific antibodies to recruit membrane-bound E3 ligases to cell surface proteins (AbTACs) have also been developed.[53]

Individual E3 ubiquitin ligases

See also

References

  1. ↑ "The ubiquitin system". Annual Review of Biochemistry 67: 425–79. 1998. doi:10.1146/annurev.biochem.67.1.425. PMID 9759494. 
  2. ↑ "Ubiquitin ligases and cell cycle control". Annual Review of Biochemistry 82: 387–414. 2013. doi:10.1146/annurev-biochem-060410-105307. PMID 23495935. 
  3. ↑ "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling". PLOS ONE 3 (1). January 2008. doi:10.1371/journal.pone.0001487. PMID 18213395. Bibcode: 2008PLoSO...3.1487L. 
  4. ↑ Békés, Miklós; Langley, David R.; Crews, Craig M. (March 2022). "PROTAC targeted protein degraders: the past is prologue" (in en). Nature Reviews Drug Discovery 21 (3): 181–200. doi:10.1038/s41573-021-00371-6. ISSN 1474-1784. PMID 35042991. 
  5. ↑ "HECT and RING finger families of E3 ubiquitin ligases at a glance". Journal of Cell Science 125 (Pt 3): 531–7. February 2012. doi:10.1242/jcs.091777. PMID 22389392. 
  6. ↑ 6.0 6.1 Walsh, Christopher (2006). Posttranslational Modification of Proteins: Expanding Nature's Inventory. Englewood, CO: Roberts. ISBN 978-0-9747077-3-0. 
  7. ↑ "Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation". Cell 115 (1): 71–82. October 2003. doi:10.1016/S0092-8674(03)00755-4. PMID 14532004. 
  8. ↑ 8.0 8.1 8.2 "Ubiquitin ligases: cell-cycle control and cancer". Nature Reviews. Cancer 6 (5): 369–81. May 2006. doi:10.1038/nrc1881. PMID 16633365. 
  9. ↑ "Systematic analysis and nomenclature of mammalian F-box proteins". Genes & Development 18 (21): 2573–80. November 2004. doi:10.1101/gad.1255304. PMID 15520277. 
  10. ↑ "Structure of ubiquitin refined at 1.8 A resolution". Journal of Molecular Biology 194 (3): 531–44. April 1987. doi:10.1016/0022-2836(87)90679-6. PMID 3041007. 
  11. ↑ 11.0 11.1 11.2 11.3 "Constructing and decoding unconventional ubiquitin chains". Nature Structural & Molecular Biology 18 (5): 520–8. May 2011. doi:10.1038/nsmb.2066. PMID 21540891. 
  12. ↑ "Signals for sorting of transmembrane proteins to endosomes and lysosomes". Annual Review of Biochemistry 72: 395–447. 2003. doi:10.1146/annurev.biochem.72.121801.161800. PMID 12651740. 
  13. ↑ "Mono- versus polyubiquitination: differential control of p53 fate by Mdm2". Science 302 (5652): 1972–5. December 2003. doi:10.1126/science.1091362. PMID 14671306. Bibcode: 2003Sci...302.1972L. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 "Ubiquitin Ligases: Structure, Function, and Regulation". Annual Review of Biochemistry 86 (1): 129–157. June 2017. doi:10.1146/annurev-biochem-060815-014922. PMID 28375744. 
  15. ↑ "Diversity of degradation signals in the ubiquitin-proteasome system". Nature Reviews Molecular Cell Biology 9 (9): 679–90. September 2008. doi:10.1038/nrm2468. PMID 18698327. 
  16. ↑ "The N-end rule pathway: emerging functions and molecular principles of substrate recognition". Nature Reviews Molecular Cell Biology 12 (11): 735–47. October 2011. doi:10.1038/nrm3217. PMID 22016057. 
  17. ↑ "The N-end rule pathway". Annual Review of Biochemistry 81: 261–89. 2012. doi:10.1146/annurev-biochem-051710-093308. PMID 22524314. 
  18. ↑ 18.0 18.1 18.2 "Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies". Current Opinion in Structural Biology 44: 101–110. June 2017. doi:10.1016/j.sbi.2016.12.015. PMID 28130986. https://discovery.dundee.ac.uk/ws/files/11471804/Manuscript_revision_1112_COSB.pdf. 
  19. ↑ "Expanding the ubiquitin code through post-translational modification". EMBO Reports 16 (9): 1071–83. September 2015. doi:10.15252/embr.201540891. PMID 26268526. 
  20. ↑ "Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response". Nature Reviews Molecular Cell Biology 14 (9): 563–80. September 2013. doi:10.1038/nrm3640. PMID 23969844. 
  21. ↑ "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation". Science 292 (5516): 468–72. April 2001. doi:10.1126/science.1059796. PMID 11292861. Bibcode: 2001Sci...292..468J. 
  22. ↑ "Plant ubiquitin ligases as signaling hubs". Nature Structural & Molecular Biology 21 (4): 293–6. April 2014. doi:10.1038/nsmb.2804. PMID 24699076. 
  23. ↑ "Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology". Frontiers in Physiology 10. 2019-02-19. doi:10.3389/fphys.2019.00104. PMID 30837888. 
  24. ↑ "RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis". Nature Reviews. Cancer 11 (9): 629–43. August 2011. doi:10.1038/nrc3120. PMID 21863050. 
  25. ↑ 25.0 25.1 "Role of E3 ubiquitin ligases in gastric cancer". World Journal of Gastroenterology 21 (3): 786–93. January 2015. doi:10.3748/wjg.v21.i3.786. PMID 25624711. 
  26. ↑ "The T309G murine double minute 2 gene polymorphism is an independent prognostic factor for patients with renal cell carcinoma". DNA and Cell Biology 34 (2): 107–12. February 2015. doi:10.1089/dna.2014.2653. PMID 25415135. 
  27. ↑ "Association between murine double minute 2 T309G polymorphism and risk of liver cancer". Tumour Biology 35 (11): 11353–7. November 2014. doi:10.1007/s13277-014-2432-9. PMID 25119589. 
  28. ↑ "Using proteomics to identify ubiquitin ligase-substrate pairs: how novel methods may unveil therapeutic targets for neurodegenerative diseases". Cellular and Molecular Life Sciences 76 (13): 2499–2510. July 2019. doi:10.1007/s00018-019-03082-9. PMID 30919022. 
  29. ↑ "E3 ubiquitin ligases". Essays in Biochemistry 41: 15–30. 2005. doi:10.1042/EB0410015. PMID 16250895. 
  30. ↑ "SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box". Cell 86 (2): 263–74. July 1996. doi:10.1016/S0092-8674(00)80098-7. PMID 8706131. 
  31. ↑ Sakamoto, K. M.; Kim, K. B.; Kumagai, A.; Mercurio, F.; Crews, C. M.; Deshaies, R. J. (2001-07-17). "Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation". Proceedings of the National Academy of Sciences of the United States of America 98 (15): 8554–8559. doi:10.1073/pnas.141230798. ISSN 0027-8424. PMID 11438690. Bibcode: 2001PNAS...98.8554S. 
  32. ↑ Lu, Jing; Qian, Yimin; Altieri, Martha; Dong, Hanqing; Wang, Jing; Raina, Kanak; Hines, John; Winkler, James D. et al. (2015-06-18). "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry & Biology 22 (6): 755–763. doi:10.1016/j.chembiol.2015.05.009. ISSN 1879-1301. PMID 26051217. 
  33. ↑ Winter, Georg E.; Buckley, Dennis L.; Paulk, Joshiawa; Roberts, Justin M.; Souza, Amanda; Dhe-Paganon, Sirano; Bradner, James E. (2015-06-19). "Phthalimide conjugation as a strategy for in vivo target protein degradation" (in en). Science 348 (6241): 1376–1381. doi:10.1126/science.aab1433. ISSN 0036-8075. PMID 25999370. Bibcode: 2015Sci...348.1376W. 
  34. ↑ Bondeson, Daniel P.; Mares, Alina; Smith, Ian E. D.; Ko, Eunhwa; Campos, Sebastien; Miah, Afjal H.; Mulholland, Katie E.; Routly, Natasha et al. (August 2015). "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature Chemical Biology 11 (8): 611–617. doi:10.1038/nchembio.1858. ISSN 1552-4469. PMID 26075522. 
  35. ↑ Zengerle, Michael; Chan, Kwok-Ho; Ciulli, Alessio (2015-08-21). "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4". ACS Chemical Biology 10 (8): 1770–1777. doi:10.1021/acschembio.5b00216. ISSN 1554-8929. PMID 26035625. 
  36. ↑ Nie, David Y.; Tabor, John R.; Li, Jianping; Kutera, Maria; St-Germain, Jonathan; Hanley, Ronan P.; Wolf, Esther; Paulakonis, Ethan et al. (December 2024). "Recruitment of FBXO22 for targeted degradation of NSD2". Nature Chemical Biology 20 (12): 1597–1607. doi:10.1038/s41589-024-01660-y. ISSN 1552-4469. PMID 38965384. 
  37. ↑ Basu, Ananya A.; Zhang, Chenlu; Riha, Isabella A.; Magassa, Assa; Campos, Miguel A.; Caldwell, Alana G.; Ko, Felicia; Zhang, Xiaoyu (December 2024). "A CRISPR activation screen identifies FBXO22 supporting targeted protein degradation". Nature Chemical Biology 20 (12): 1608–1616. doi:10.1038/s41589-024-01655-9. ISSN 1552-4469. PMID 38965383. 
  38. ↑ Kagiou, Chrysanthi; Cisneros, Jose A.; Farnung, Jakob; Liwocha, Joanna; Offensperger, Fabian; Dong, Kevin; Yang, Ka; Tin, Gary et al. (2024-06-26). "Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation" (in en). Nature Communications 15 (1): 5409. doi:10.1038/s41467-024-49739-3. ISSN 2041-1723. PMID 38926334. Bibcode: 2024NatCo..15.5409K. 
  39. ↑ Scott, Daniel C.; Dharuman, Suresh; Griffith, Elizabeth; Chai, Sergio C.; Ronnebaum, Jarrid; King, Moeko T.; Tangallapally, Rajendra; Lee, Chan et al. (2024-10-12). "Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2" (in en). Nature Communications 15 (1): 8829. doi:10.1038/s41467-024-52966-3. ISSN 2041-1723. PMID 39396041. Bibcode: 2024NatCo..15.8829S. 
  40. ↑ Ito, Takumi; Ando, Hideki; Suzuki, Takayuki; Ogura, Toshihiko; Hotta, Kentaro; Imamura, Yoshimasa; Yamaguchi, Yuki; Handa, Hiroshi (2010-03-12). "Identification of a Primary Target of Thalidomide Teratogenicity". Science 327 (5971): 1345–1350. doi:10.1126/science.1177319. PMID 20223979. Bibcode: 2010Sci...327.1345I. https://www.science.org/doi/10.1126/science.1177319. 
  41. ↑ Choi, J.; Chen, J.; Schreiber, S. L.; Clardy, J. (1996-07-12). "Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP". Science 273 (5272): 239–242. doi:10.1126/science.273.5272.239. ISSN 0036-8075. PMID 8662507. Bibcode: 1996Sci...273..239C. 
  42. ↑ Liu, Jun; Farmer, Jesse D.; Lane, Willam S.; Friedman, Jeff; Weissman, Irving; Schreiber, Stuart L. (1991-08-23). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes" (in English). Cell 66 (4): 807–815. doi:10.1016/0092-8674(91)90124-H. ISSN 0092-8674. PMID 1715244. https://www.cell.com/cell/abstract/0092-8674(91)90124-H. 
  43. ↑ Bushman, Jonathan W.; Deng, Weixian; Samarasinghe, Kusal T. G.; Liu, Han-Yuan; Li, Shiqian; Vaish, Amit; Golkar, Alex; Ou, Shu-Ching et al. (2025-03-19) (in en), Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq, bioRxiv, doi:10.1101/2025.03.19.644003, https://www.biorxiv.org/content/10.1101/2025.03.19.644003v1, retrieved 2025-04-07 
  44. ↑ Razumkov, Hlib; Jiang, Zixuan; Baek, Kheewoong; You, Inchul; Geng, Qixiang; Donovan, Katherine A.; Tang, Michelle T.; Metivier, Rebecca J. et al. (2024-11-20). "Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library". Journal of the American Chemical Society 146 (46): 31433–31443. doi:10.1021/jacs.4c06127. ISSN 0002-7863. PMID 39499896. Bibcode: 2024JAChS.14631433R. 
  45. ↑ Zhuang, Zhe; Byun, Woong Sub; Chrustowicz, Jakub; Kozicka, Zuzanna; Li, Veronica L.; Abeja, Dinah M.; Donovan, Katherine A.; Sepic, Sara et al. (2024-09-26) (in en), Charged Molecular Glue Discovery Enabled by Targeted Degron Display, bioRxiv, doi:10.1101/2024.09.24.614843, https://www.biorxiv.org/content/10.1101/2024.09.24.614843v1, retrieved 2025-04-07 
  46. ↑ Wang, Zefeng; Shaabani, Shabnam; Gao, Xiang; Ng, Yuen Lam Dora; Sapozhnikova, Valeriia; Mertins, Philipp; Krönke, Jan; Dömling, Alexander (2023-12-19). "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery" (in en). Nature Communications 14 (1): 8437. doi:10.1038/s41467-023-43614-3. ISSN 2041-1723. PMID 38114468. Bibcode: 2023NatCo..14.8437W. 
  47. ↑ Toriki, Ethan S.; Papatzimas, James W.; Nishikawa, Kaila; Dovala, Dustin; Frank, Andreas O.; Hesse, Matthew J.; Dankova, Daniela; Song, Jae-Geun et al. (2023-05-24). "Rational Chemical Design of Molecular Glue Degraders". ACS Central Science 9 (5): 915–926. doi:10.1021/acscentsci.2c01317. ISSN 2374-7943. PMID 37252349. 
  48. ↑ Baek, Kheewoong; Metivier, Rebecca J.; Roy Burman, Shourya S.; Bushman, Jonathan W.; Yoon, Hojong; Lumpkin, Ryan J.; Abeja, Dinah M.; Lakshminarayan, Megha et al. (2024-10-04). "Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics". BioRxiv: The Preprint Server for Biology. doi:10.1101/2024.09.11.612438. ISSN 2692-8205. PMID 39314457. 
  49. ↑ Lim, Shuhui; Khoo, Regina; Peh, Khong Ming; Teo, Jinkai; Chang, Shih Chieh; Ng, Simon; Beilhartz, Greg L.; Melnyk, Roman A. et al. (2020-03-17). "bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)". Proceedings of the National Academy of Sciences 117 (11): 5791–5800. doi:10.1073/pnas.1920251117. PMID 32123106. Bibcode: 2020PNAS..117.5791L. 
  50. ↑ Fletcher, Alice; Clift, Dean; de Vries, Emma; Martinez Cuesta, Sergio; Malcolm, Timothy; Meghini, Francesco; Chaerkady, Raghothama; Wang, Junmin et al. (2023-11-04). "A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation" (in en). Nature Communications 14 (1): 7093. doi:10.1038/s41467-023-42546-2. ISSN 2041-1723. PMID 37925433. Bibcode: 2023NatCo..14.7093F. 
  51. ↑ Ou, Lisha; Setegne, Mekedlawit T.; Elliot, Jeandele; Shen, Fangfang; Dassama, Laura M. K. (2025-02-26). "Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics". Chemical Reviews 125 (4): 2120–2183. doi:10.1021/acs.chemrev.4c00595. ISSN 1520-6890. PMID 39818743. 
  52. ↑ Chan, Alexander; Haley, Rebecca M.; Najar, Mohd Altaf; Gonzalez-Martinez, David; Bugaj, Lukasz J.; Burslem, George M.; Mitchell, Michael J.; Tsourkas, Andrew (2024-07-10). "Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins" (in en). Nature Communications 15 (1): 5808. doi:10.1038/s41467-024-50235-x. ISSN 2041-1723. PMID 38987546. Bibcode: 2024NatCo..15.5808C. 
  53. ↑ Cotton, Adam D.; Nguyen, Duy P.; Gramespacher, Josef A.; Seiple, Ian B.; Wells, James A. (2021-01-20). "Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1". Journal of the American Chemical Society 143 (2): 593–598. doi:10.1021/jacs.0c10008. ISSN 0002-7863. PMID 33395526. Bibcode: 2021JAChS.143..593C. 



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