Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

Horn-Ghetko, Daniel; Krist, David T.; Prabu, J. Rajan; Baek, Kheewoong; Mulder, Monique P. C.; Klügel, Maren; Scott, Daniel C.; Ovaa, Huib; Kleiger, Gary; Schulman, Brenda A.

doi:10.1038/s41586-021-03197-9

Cited by 187Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsEnzyme Structure and Function

Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

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Horn-Ghetko, Daniel, Krist, David T., Prabu, J. Rajan, Baek, Kheewoong, Mulder, Monique P. C., Klügel, Maren, Scott, Daniel C., Ovaa, Huib +2 more·2021·Nature

DOI 10.1038/s41586-021-03197-9PMC PMC7904520

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Abstract

E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates 1,2. However, rather than functioning individually, many neddylated cullin–RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family—which together account for nearly half of all ubiquitin ligases in humans—form E3–E3 super-assemblies 3–7. Here, by studying CRLs in the SKP1–CUL1–F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3–E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3–E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3–E3 super-assembly may therefore underlie widespread ubiquitylation.

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RING and RBR ligases have recently been shown to work in unison to mediate substrate ubiquitylation in a site-specific manner.
“RING and RBR ligases have recently been shown to work in unison to mediate substrate ubiquitylation in a site-specific manner116,117.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [117]
The exact mechanism of ubiquitylation for MRLs is not as well understood as the mechanism for CRLs, for which substrate recruitment by multiple adaptors and the molecular details of Ub transfer from E2-Ub to the target have been extensively characterized at the atomic level of an entire CRL1 complex.
“The exact mechanism of ubiquitylation for MRLs is not as well understood as the mechanism for CRLs, for which substrate recruitment by multiple adaptors and the molecular details of Ub transfer from E2–Ub to the target has been extensively characterized at the atomic level of an entire CRL1 complex106,117.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [117]

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Dove, K. K., Olszewski, J. L., Martino, L., Duda, D. M., Wu, X. S., Miller, D. J., Reiter, K. H., Rittinger, K., Schulman, B. A., & Klevit, R. E. (2017) · Structure · doi:10.1016/j.str.2017.04.013 · Cited by 52 · see citing works
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Structural Biology of CRL Ubiquitin Ligases
Rusnac, D.-V., & Zheng, N. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-1025-0_2 · Cited by 52 · see citing works
Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development
Dove, K. K., Kemp, H. A., Bona, K. R. D., Reiter, K. H., Milburn, L. J., Camacho, D., Fay, D. S., Miller, D. L., & Klevit, R. E. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705060114 · Cited by 37 · see citing works

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PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
An expanded lexicon for the ubiquitin code
Đikić, I., & Schulman, B. A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00543-1 · Cited by 417 · see citing works
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Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis
Harper, J. W., & Schulman, B. A. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-090120-013613 · Cited by 252 · see citing works
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Ubiquitin ligases: guardians of mammalian development
Walma, D. A. C., Chen, Z., Bullock, A. N., & Yamada, K. M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00448-5 · Cited by 212 · see citing works
Protein neddylation and its role in health and diseases
Zhang, S., Yu, Q., Li, Z., Zhao, Y., & Sun, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01800-9 · Cited by 171 · see citing works
An E3 ligase guide to the galaxy of small-molecule-induced protein degradation
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Structural insights into Ubr1-mediated N-degron polyubiquitination
Pan, M., Zheng, Q., Wang, T., Liang, L., Mao, J., Zuo, C., Ding, R., Ai, H., Xie, Y., Si, D., et al. (2021) · Nature · doi:10.1038/s41586-021-04097-8 · Cited by 131 · see citing works
How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini
Sherpa, D., Chrustowicz, J., & Schulman, B. A. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.004 · Cited by 123 · see citing works
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The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation
Riching, K. M., Caine, E. A., Urh, M., & Daniels, D. L. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00339b · Cited by 105 · see citing works
Insights in Post-Translational Modifications: Ubiquitin and SUMO
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Chemical Synthesis of Activity‐Based E2‐Ubiquitin Probes for the Structural Analysis of E3 Ligase‐Catalyzed Transthiolation
Liang, L., Chu, G., Qu, Q., Zuo, C., Mao, J., Zheng, Q., Chen, J., Meng, X., Jing, Y., Deng, H., et al. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202105870 · Cited by 85 · see citing works
A new dawn beyond lysine ubiquitination
Squair, D. R., & Virdee, S. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01088-2 · Cited by 81 · see citing works
Mechanism of degrader-targeted protein ubiquitinability
Crowe, C., Nakasone, M. A., Chandler, S., Craigon, C., Sathe, G. J., Tatham, M. H., Makukhin, N., Hay, R. T., & Ciulli, A. (2024) · Science Advances · doi:10.1126/sciadv.ado6492 · Cited by 81 · see citing works
Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options
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Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs
Bai, N., Riching, K. M., Makaju, A., Wu, H., Acker, T. M., Ou, S.-C., Zhang, Y., Shen, X., Bulloch, D. N., Rui, H., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101653 · Cited by 77 · see citing works
Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5
Hehl, L. A., Horn‐Ghetko, D., Prabu, J. R., Vollrath, R., Vu, D. T., Berrocal, D. A. P., Mulder, M. P. C., van Noort, G. J. V. D. H., & Schulman, B. A. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01414-2 · Cited by 72 · see citing works
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The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation
Xu, P., Liu, Y., Liu, C., Guey, B., Li, L., Mélénec, P., Ricci, J., & Ablasser, A. (2024) · Nature · doi:10.1038/s41586-024-07112-w · Cited by 77 · see citing works
The structural basis for HIV-1 Vif antagonism of human APOBEC3G
Li, Y.-L., Langley, C. A., Azumaya, C. M., Echeverria, I., Chesarino, N. M., Emerman, M., Cheng, Y., & Gross, J. D. (2023) · Nature · doi:10.1038/s41586-023-05779-1 · Cited by 74 · see citing works
The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS
Xiong, T.-C., Wei, M., Li, F., Shi, M., Gan, H., Tang, Z., Dong, H., Liuyu, T., Gao, P., Zhong, B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33671-5 · Cited by 70 · see citing works
Recruitment of FBXO22 for targeted degradation of NSD2
Nie, Y., Tabor, J. R., Li, J., Kutera, M., St‐Germain, J. R., Hanley, R. P., Wolf, E., Paulаkonis, E., Kenney, T. M. G., Duan, S., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01660-y · Cited by 70 · see citing works
The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family
Wang, X. S., Cotton, T. R., Trevelyan, S. J., Richardson, L. W., Lee, W. T., Silke, J., & Lechtenberg, B. C. (2023) · Nature Communications · doi:10.1038/s41467-023-35871-z · Cited by 64 · see citing works
CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation
Kostrhon, S., Prabu, J. R., Baek, K., Horn‐Ghetko, D., von Gronau, S., Klügel, M., Basquin, J., Alpi, A. F., & Schulman, B. A. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00858-8 · Cited by 62 · see citing works
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E3 ubiquitin ligases in signaling, disease, and therapeutics
Ebadi, P., Stratton, C. M., & Olsen, S. K. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.07.009 · Cited by 65 · see citing works
Synthetic E2-Ub-nucleosome conjugates for studying nucleosome ubiquitination
Ai, H., Tong, Z., Deng, Z., Tian, J., Zhang, L., Sun, M., Du, Y., Xu, Z., Shi, Q., Liang, L., et al. (2023) · Chem · doi:10.1016/j.chempr.2023.01.012 · Cited by 58 · see citing works
CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis
Samelson, A. J., Ariqat, N., McKetney, J., Rohanitazangi, G., Bravo, C., Bose, R., Travaglini, K. J., Lam, V. L., Goodness, D., Ta, T., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.038 · Cited by 65 · see citing works
Structural Characterization of Degrader-Induced Ternary Complexes Using Hydrogen–Deuterium Exchange Mass Spectrometry and Computational Modeling: Implications for Structure-Based Design
Eron, S. J., Huang, H., Agafonov, R. V., Fitzgerald, M. E., Patel, J., Michael, R. E., Lee, T. D., Hart, A. A., Shaulsky, J., Nasveschuk, C. G., et al. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00376 · Cited by 57 · see citing works
The ubiquitin ligation machinery in the defense against bacterial pathogens
Tripathi‐Giesgen, I., Behrends, C., & Alpi, A. F. (2021) · EMBO Reports · doi:10.15252/embr.202152864 · Cited by 51 · see citing works
Ubiquitin–proteasome system as a target for anticancer treatment—an update
Kim, Y. J., Lee, Y., Shin, H. Y., Hwang, S., Park, J., & Song, E. J. (2023) · Archives of Pharmacal Research · doi:10.1007/s12272-023-01455-0 · Cited by 57 · see citing works
Decoding the messaging of the ubiquitin system using chemical and protein probes
Henneberg, L. T., & Schulman, B. A. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.009 · Cited by 52 · see citing works
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TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer
Zhang, R., Shen, Y., Zhang, Q., Feng, X., Liu, X., Huo, X., Sun, J., & Hao, J. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06383-x · Cited by 53 · see citing works
Systemwide disassembly and assembly of SCF ubiquitin ligase complexes
Baek, K., Scott, D. C., Henneberg, L. T., King, M. T., Mann, M., & Schulman, B. A. (2023) · Cell · doi:10.1016/j.cell.2023.02.035 · Cited by 47 · see citing works
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Mechanistic insights into nucleosomal H2B monoubiquitylation mediated by yeast Bre1-Rad6 and its human homolog RNF20/RNF40-hRAD6A
Deng, Z., Ai, H., Sun, M., Tong, Z., Du, Y., Qu, Q., Zhang, L., Xu, Z., Tao, S., Shi, Q., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.08.001 · Cited by 47 · see citing works
Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting
Li, J., Purser, N., Liwocha, J., Scott, D. C., Byers, H. A., Steigenberger, B. A., Hill, S., Tripathi‐Giesgen, I., Hinkle, T. B., Hansen, F. M., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.022 · Cited by 45 · see citing works
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Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases
Liwocha, J., Li, J., Purser, N., Rattanasopa, C., Maiwald, S. A., Krist, D. T., Scott, D. C., Steigenberger, B. A., Prabu, J. R., Schulman, B. A., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01206-1 · Cited by 44 · see citing works
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Sugar-mediated non-canonical ubiquitination impairs Nrf1/NFE2L1 activation
Yoshida, Y., Takahashi, T., Ishii, N., Matsuo, I., Takahashi, S., Inoue, H., Endo, A., Tsuchiya, H., Okada, M., Ando, C., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.07.013 · Cited by 42 · see citing works
Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Chen, Z., Ioris, R. M., Richardson, S., Van Ess, A. N., Vendrell, I., Kessler, B. M., Buffa, F. M., Busino, L., Clifford, S. C., Bullock, A. N., et al. (2022) · Cell Death & Differentiation · doi:10.1038/s41418-022-00983-4 · Cited by 41 · see citing works
Structure of the human UBR5 E3 ubiquitin ligase
Wang, F., He, Q., Zhan, W., Yu, Z., Finkin-Groner, E., Ma, X., Lin, G., & Li, H. (2023) · Structure · doi:10.1016/j.str.2023.03.010 · Cited by 39 · see citing works
Parkin and mitochondrial signalling
Connelly, E. M., Frankel, K. S., & Shaw, G. S. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110631 · Cited by 37 · see citing works
Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216
Cotton, T. R., Cobbold, S. A., Bernardini, J. P., Richardson, L. W., Wang, X. S., & Lechtenberg, B. C. (2022) · Molecular Cell · doi:10.1016/j.molcel.2021.12.005 · Cited by 36 · see citing works
Structure-guided engineering enables E3 ligase-free and versatile protein ubiquitination via UBE2E1
Wu, X., Du, Y., Liang, L.-J., Ding, R., Zhang, T., Cai, H., Tian, X., Pan, M., & Liu, L. (2024) · Nature Communications · doi:10.1038/s41467-024-45635-y · Cited by 34 · see citing works
Photocaging of Activity‐Based Ubiquitin Probes via a C‐Terminal Backbone Modification Strategy
Wang, Y., Chen, J., Xiao, H., Meng, X., Cai, H., Wang, R., Shi, J. M., Deng, H., Liu, L., & Li, Y. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202203792 · Cited by 33 · see citing works
A pair of E3 ubiquitin ligases control immunity and flowering by targeting different ELF3 proteins in rice
Xu, X. H., Shi, X., You, X., Hao, Z., Wang, R., Wang, M., He, F., Peng, S., Tao, H., Liu, Z., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.06.013 · Cited by 31 · see citing works
Cell cycle regulation by complex nanomachines
Koliopoulos, M. G., & Alfieri, C. (2021) · FEBS Journal · doi:10.1111/febs.16082 · Cited by 31 · see citing works
High-throughput ligand diversification to discover chemical inducers of proximity
Shaum, J. B., Ordoño, M. M. I., Steen, E. A., Wenge, D. V., Cheong, H., Janowski, J., Hunkeler, M., Bilotta, E. M., Rutter, Z. J., Barta, P. A., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02137-2 · Cited by 30 · see citing works
TIMELESS‐TIPIN and UBXN‐3 promote replisome disassembly during DNA replication termination in Caenorhabditis elegans
Xia, Y., Fujisawa, R., Deegan, T. D., Sonneville, R., & Labib, K. P. M. (2021) · The EMBO Journal · doi:10.15252/embj.2021108053 · Cited by 28 · see citing works
Structure of CRL7FBXW8 reveals coupling with CUL1–RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation
Hopf, L. V. M., Baek, K., Klügel, M., von Gronau, S., Xiong, Y., & Schulman, B. A. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00815-6 · Cited by 28 · see citing works
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Exaptation of Inactivated Host Enzymes for Structural Roles in Orthopoxviruses and Novel Folds of Virus Proteins Revealed by Protein Structure Modeling
Mutz, P., Resch, W., Faure, G., Senkevich, T. G., Koonin, E. V., & Moss, B. (2023) · mBio · doi:10.1128/mbio.00408-23 · Cited by 26 · see citing works
The new direction of drug development: Degradation of undruggable targets through targeting chimera technology
Liang, X., Ren, H., Han, F., Liang, R., Zhao, J., & Liu, H. S. (2023) · Medicinal Research Reviews · doi:10.1002/med.21992 · Cited by 28 · see citing works
Mechanism of nucleosomal H2A K13/15 monoubiquitination and adjacent dual monoubiquitination by RNF168
Ai, H., Tong, Z., Deng, Z., Shi, Q., Tao, S., Sun, G., Liang, J., Sun, M., Wu, X., Zheng, Q., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01750-x · Cited by 32 · see citing works
Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2
Scott, D. C., Dharuman, S., Griffith, E. C., Chai, S. C., Ronnebaum, J., King, M. T., Tangallapally, R. P., Lee, C., Gee, C. T., Yang, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52966-3 · Cited by 28 · see citing works
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Advances in the chemical synthesis of human proteoforms
Yang, Z.-Y., Xiao, Y., Shi, Y., & Liu, L. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2860-5 · Cited by 22 · see citing works
Activity-based profiling of cullin–RING E3 networks by conformation-specific probes
Henneberg, L. T., Singh, J., Duda, D. M., Baek, K., Yanishevski, D., Murray, P. J., Mann, M., Sidhu, S. S., & Schulman, B. A. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01392-5 · Cited by 31 · see citing works
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Dynamic molecular architecture and substrate recruitment of cullin3–RING E3 ligase CRL3KBTBD2
Hu, Y., Zhang, Z., Mao, Q., Zhang, X., Hao, A., Xun, Y., Wang, Y., Han, L., Zhan, W., Liu, Q., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01182-6 · Cited by 26 · see citing works
Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases
Diaz, S., Wang, K., Sjögren, B., & Liu, X. (2022) · Biomolecules · doi:10.3390/biom12030416 · Cited by 26 · see citing works
The E3-ome gene-centric compendium reveals the human E3 ligase landscape
Chua, N. K., González-Robles, T. J., Reddington, C. J., Dudley-Fraser, J., Birkinshaw, R. W., Han, J., Solano, A. N., Wong, S. W., Kochańczyk, T., Peter, J. J., et al. (2026) · Cell · doi:10.1016/j.cell.2026.01.029 · Cited by 27 · see citing works
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Adaptive exchange sustains cullin–RING ubiquitin ligase networks and proper licensing of DNA replication
Zhang, Y., Jost, M., Pak, R. A., Lu, D., Li, J., Lomenick, B., Garbis, S. D., Li, C.-M., Weissman, J. S., Lipford, J. R., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2205608119 · Cited by 23 · see citing works
Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange
Shaaban, M., Clapperton, J. A., Ding, S., Kunzelmann, S., Mäeots, M.-E., Maslen, S., Skehel, M. J., & Enchev, R. I. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.05.034 · Cited by 24 · see citing works
A bifunctional molecule-assisted synthesis of mimics for use in probing the ubiquitination system
Zheng, Q., Wang, T., Mao, J., Chu, G., Liang, L., Jing, Y., Zuo, C., Yu, Y., Hu, H., & Pan, M. (2022) · Nature Protocols · doi:10.1038/s41596-022-00761-z · Cited by 24 · see citing works
New classes of E3 ligases illuminated by chemical probes
Horn‐Ghetko, D., & Schulman, B. A. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102341 · Cited by 23 · see citing works
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Germline CDKN1B variant type and site are associated with phenotype in MEN4
Halperin, R., Arnon, L., Nasirov, S., Friedensohn, L., Gershinsky, M., Telerman, A., Friedman, E., Bernstein‐Molho, R., & Tirosh, A. (2022) · Endocrine Related Cancer · doi:10.1530/erc-22-0174 · Cited by 23 · see citing works
Historical perspective and progress on protein ubiquitination at glutamatergic synapses
Mabb, A. M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108690 · Cited by 24 · see citing works
USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy
Wu, Q., Wang, Z., Chen, S., She, X., Zhu, S., Li, P., Liu, L., Zhao, C., Li, K., Liu, A., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03009-0 · Cited by 22 · see citing works
ECHDC2 inhibits the proliferation of gastric cancer cells by binding with NEDD4 to degrade MCCC2 and reduce aerobic glycolysis
He, J., Yi, J., Ji, L., Dai, L., Chen, Y., & Xue, W. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00832-9 · Cited by 22 · see citing works
Promotion of RNF168‐Mediated Nucleosomal H2A Ubiquitylation by Structurally Defined K63‐Polyubiquitylated Linker Histone H1
Shi, Q., Deng, Z., Zhang, L., Tong, Z., Li, J., Chu, G., Ai, H., & Liu, L. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202413651 · Cited by 22 · see citing works
Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Enrico, T. P., Stallaert, W., Wick, E. T., Ngoi, P., Wang, X., Rubin, S. M., Brown, N. G., Purvis, J. E., & Emanuele, M. J. (2021) · eLife · doi:10.7554/elife.70691 · Cited by 21 · see citing works
Structural mechanisms of autoinhibition and substrate recognition by the ubiquitin ligase HACE1
Düring, J., Wolter, M., Toplak, J. J., Torres, C., Dybkov, O., Fokkens, T. J., Bohnsack, K. E., Urlaub, H., Steinchen, W., Dienemann, C., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01203-4 · Cited by 20 · see citing works
Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G
Kouno, T., Shibata, S., Shigematsu, M., Hyun, J., Kim, T. G., Matsuo, H., & Wolf, M. (2023) · Nature Communications · doi:10.1038/s41467-023-39796-5 · Cited by 21 · see citing works
RUNX3 Meets the Ubiquitin-Proteasome System in Cancer
Toska, A., Modi, N., & Chen, L. (2023) · Cells · doi:10.3390/cells12050717 · Cited by 20 · see citing works
SMRT and Illumina RNA Sequencing and Characterization of a Key NAC Gene LoNAC29 during the Flower Senescence in Lilium oriental ‘Siberia’
Luo, J., Li, R., Xu, X., Niu, H., Zhang, Y., & Wang, C. (2021) · Genes · doi:10.3390/genes12060869 · Cited by 19 · see citing works
Genome-wide identification, evolutionary and functional analyses of KFB family members in potato
Tang, R., Dong, H., He, L., Li, P., Shi, Y., Yang, Q., Jia, X., & Li, X. (2022) · BMC Plant Biology · doi:10.1186/s12870-022-03611-y · Cited by 19 · see citing works
Cryo-EM structure of SKP1-SKP2-CKS1 in complex with CDK2-cyclin A-p27KIP1
Rowland, R. J., Heath, R., Maskell, D. P., Thompson, R. F., Ranson, N. A., Blaza, J. N., Endicott, J., Noble, M. E. M., & Salamina, M. (2023) · Scientific Reports · doi:10.1038/s41598-023-37609-9 · Cited by 18 · see citing works
Noncanonical assembly, neddylation and chimeric cullin–RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex
Horn‐Ghetko, D., Hopf, L. V. M., Tripathi‐Giesgen, I., Du, J., Kostrhon, S., Vu, D. T., Beier, V., Steigenberger, B. A., Prabu, J. R., Stier, L. J., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01257-y · Cited by 18 · see citing works
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ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213
Ahel, J., Balci, A., Faas, V., Grabarczyk, D. B., Harmo, R., Squair, D. R., Zhang, J., Roitinger, E., Lamoliatte, F., Mathur, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59444-4 · Cited by 17 · see citing works
FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1‐Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis
Wu, T., Wang, Y., Shen, B., Guo, K., Zhu, Z., Liang, Y., Zeng, J., & Wu, D. (2025) · Advanced Science · doi:10.1002/advs.202506150 · Cited by 18 · see citing works
Structural insights into the ubiquitylation strategy of the oligomeric CRL2FEM1B E3 ubiquitin ligase
Dai, Z., Liang, L., Wang, W., Zuo, P., Yu, S. J., Liu, Y., Zhao, X., Lu, Y., Jin, Y., Zhang, F., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00047-y · Cited by 18 · see citing works
Diversity of structure and function in Cullin E3 ligases
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Authors: Horn-Ghetko, D., Krist, D. T., Prabu, J. R., Baek, K., Mulder, M. P. C., Klügel, M., Scott, D. C., Ovaa, H., Kleiger, G., & Schulman, B. A.
Affiliations: Max Planck Institute of Biochemistry (DE)
Leiden University Medical Center (NL)
St. Jude Children's Research Hospital (US)
University of Nevada, Las Vegas (US)
Corresponding author: Schulman, Brenda A.
ORCID: Horn-Ghetko, Daniel
Krist, David T.
Prabu, J. Rajan
Baek, Kheewoong
Mulder, Monique P. C.
Scott, Daniel C.
Ovaa, Huib
Kleiger, Gary
Schulman, Brenda A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2021-02-03
Volume: 590
Issue: 7847
Pages: 671-676
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-021-03197-9
PMC: PMC7904520
OpenAlex: W3129120649
Cited by: 187
References: 71
Citations by year: 2026: 22 · 2025: 32 · 2024: 51 · 2023: 28 · 2022: 35 · 2021: 18 · 2014: 1
FWCI: 10.44
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by)
Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion, cc-by)
Funders: American Lebanese Syrian Associated Charities
Deutsche Forschungsgemeinschaft (SCHU 3196/1‐1, SCHU 3196/1)
Max-Planck-Gesellschaft
National Institutes of Health (H2020)
Horizon 2020 Framework Programme (789016-NEDD8Activate)
Leibniz-Gemeinschaft
National Institute of General Medical Sciences (R15GM117555)
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
Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords: E3 ubiquitin ligase, F-box protein, UBE2L3, ubiquitin transfer, cryo-electron microscopy, substrate recognition
MeSH terms: Allosteric Regulation, Humans, Phosphorylation, Substrate Specificity, Cyclin E, Cryoelectron Microscopy, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, F-Box Proteins, SKP Cullin F-Box Protein Ligases, Ubiquitination, Biocatalysis

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Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

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