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

<div class='caption-title'>Snapshots that represent intermediates during ARIH1-catalysed ubiquitylation of the phosphorylated cyclin E substrate of SCFFBXW7.</div>
<div class='caption-title'>Amalgamated intermolecular E3–E3act super-domain and E3–E3 platform activate neddylated SCF–ARIH1 ubiquitylation.</div>
<div class='caption-title'>ARIH1 ubiquitylation of a range of substrates recruited to diverse F-box proteins.</div>
Horn-Ghetko D, Krist DT, Prabu JR, Baek K, Mulder MPC, Klügel M, Scott DC, Ovaa H, Kleiger G, Schulman BA
OpenAccess logo Nature 590 671-676 (2021)
Related entries: 7b5m, 7b5n, 7b5r, 7b5s

Cited: 49 times
EuropePMC logo PMID: 33536622

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 substrates1,2. 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-assemblies3-7. 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.

Articles - 7b5l mentioned but not cited (8)

  1. Cullin-independent recognition of HHARI substrates by a dynamic RBR catalytic domain. Reiter KH, Zelter A, Janowska MK, Riffle M, Shulman N, MacLean BX, Tamura K, Chambers MC, MacCoss MJ, Davis TN, Guttman M, Brzovic PS, Klevit RE. Structure 30 1269-1284.e6 (2022)
  2. CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Kostrhon S, Prabu JR, Baek K, Horn-Ghetko D, von Gronau S, Klügel M, Basquin J, Alpi AF, Schulman BA. Nat Chem Biol 17 1075-1083 (2021)
  3. Activity-based profiling of cullin-RING E3 networks by conformation-specific probes. Henneberg LT, Singh J, Duda DM, Baek K, Yanishevski D, Murray PJ, Mann M, Sidhu SS, Schulman BA. Nat Chem Biol (2023)
  4. research-article Activity-based profiling of cullin-RING ligase networks by conformation-specific probes. Henneberg LT, Singh J, Duda DM, Baek K, Yanishevski D, Murray PJ, Mann M, Sidhu SS, Schulman B. bioRxiv 2023.01.14.524048 (2023)
  5. Cryo-EM structure of SKP1-SKP2-CKS1 in complex with CDK2-cyclin A-p27KIP1. Rowland RJ, Heath R, Maskell D, Thompson RF, Ranson NA, Blaza JN, Endicott JA, Noble MEM, Salamina M. Sci Rep 13 10718 (2023)
  6. Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs. Bai N, Riching KM, Makaju A, Wu H, Acker TM, Ou SC, Zhang Y, Shen X, Bulloch DN, Rui H, Gibson BW, Daniels DL, Urh M, Rock BM, Humphreys SC. J Biol Chem 298 101653 (2022)
  7. Systemwide disassembly and assembly of SCF ubiquitin ligase complexes. Baek K, Scott DC, Henneberg LT, King MT, Mann M, Schulman BA. Cell 186 1895-1911.e21 (2023)
  8. The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family. Wang XS, Cotton TR, Trevelyan SJ, Richardson LW, Lee WT, Silke J, Lechtenberg BC. Nat Commun 14 168 (2023)


Reviews citing this publication (17)

  1. PROTAC targeted protein degraders: the past is prologue. Békés M, Langley DR, Crews CM. Nat Rev Drug Discov 21 181-200 (2022)
  2. Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis. Harper JW, Schulman BA. Annu Rev Biochem 90 403-429 (2021)
  3. An expanded lexicon for the ubiquitin code. Dikic I, Schulman BA. Nat Rev Mol Cell Biol 24 273-287 (2023)
  4. How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini. Sherpa D, Chrustowicz J, Schulman BA. Mol Cell 82 1424-1438 (2022)
  5. Decoding the messaging of the ubiquitin system using chemical and protein probes. Henneberg LT, Schulman BA. Cell Chem Biol 28 889-902 (2021)
  6. The ubiquitin ligation machinery in the defense against bacterial pathogens. Tripathi-Giesgen I, Behrends C, Alpi AF. EMBO Rep 22 e52864 (2021)
  7. A new dawn beyond lysine ubiquitination. Squair DR, Virdee S. Nat Chem Biol 18 802-811 (2022)
  8. The E3 Ubiquitin Ligase Fbxo4 Functions as a Tumor Suppressor: Its Biological Importance and Therapeutic Perspectives. Qie S. Cancers (Basel) 14 2133 (2022)
  9. 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. Nat Protoc 18 530-554 (2023)
  10. From seeds to trees: how E2 enzymes grow ubiquitin chains. Middleton AJ, Day CL. Biochem Soc Trans 51 353-362 (2023)
  11. Historical perspective and progress on protein ubiquitination at glutamatergic synapses. Mabb AM. Neuropharmacology 196 108690 (2021)
  12. Insights in Post-Translational Modifications: Ubiquitin and SUMO. Salas-Lloret D, González-Prieto R. Int J Mol Sci 23 3281 (2022)
  13. Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2. Barik S. Int J Mol Sci 23 489 (2022)
  14. RUNX3 Meets the Ubiquitin-Proteasome System in Cancer. Toska A, Modi N, Chen LF. Cells 12 717 (2023)
  15. Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases. Diaz S, Wang K, Sjögren B, Liu X. Biomolecules 12 416 (2022)
  16. Ubiquitin ligases: guardians of mammalian development. Cruz Walma DA, Chen Z, Bullock AN, Yamada KM. Nat Rev Mol Cell Biol 23 350-367 (2022)
  17. Ubiquitin-proteasome system as a target for anticancer treatment-an update. Kim YJ, Lee Y, Shin H, Hwang S, Park J, Song EJ. Arch Pharm Res 46 573-597 (2023)

Articles citing this publication (24)

  1. TIMELESS-TIPIN and UBXN-3 promote replisome disassembly during DNA replication termination in Caenorhabditis elegans. Xia Y, Fujisawa R, Deegan TD, Sonneville R, Labib KPM. EMBO J 40 e108053 (2021)
  2. Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2. Enrico TP, Stallaert W, Wick ET, Ngoi P, Wang X, Rubin SM, Brown NG, Purvis JE, Emanuele MJ. Elife 10 e70691 (2021)
  3. 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 TG, Koonin EV, Moss B. mBio 14 e0040823 (2023)
  4. Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5. Hehl LA, Horn-Ghetko D, Prabu JR, Vollrath R, Vu DT, Pérez Berrocal DA, Mulder MPC, van der Heden van Noort GJ, Schulman BA. Nat Chem Biol (2023)
  5. A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer. Li Y, Chu Y, Shi G, Wang X, Ye W, Shan C, Wang D, Zhang D, He W, Jiang J, Ma S, Han Y, Zhao Z, Du S, Chen Z, Li Z, Yang Y, Wang C, Xu X, Wu H. Acta Pharm Sin B 12 4165-4179 (2022)
  6. A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy. Bano I, Malhi M, Zhao M, Giurgiulescu L, Sajjad H, Kieliszek M. 3 Biotech 12 103 (2022)
  7. Adaptive exchange sustains cullin-RING ubiquitin ligase networks and proper licensing of DNA replication. Zhang Y, Jost M, Pak RA, Lu D, Li J, Lomenick B, Garbis SD, Li CM, Weissman JS, Lipford JR, Deshaies RJ. Proc Natl Acad Sci U S A 119 e2205608119 (2022)
  8. CAND1 is required for pollen viability in Arabidopsis thaliana-a test of the adaptive exchange hypothesis. Li L, Garsamo M, Yuan J, Wang X, Lam SH, Varala K, Boavida LC, Zhou Y, Liu X. Front Plant Sci 13 866086 (2022)
  9. Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase. Purser N, Tripathi-Giesgen I, Li J, Scott DC, Horn-Ghetko D, Baek K, Schulman BA, Alpi AF, Kleiger G. Biochem J 480 1817-1831 (2023)
  10. Cysteine Redox Chemistry in Peptide Self-Assembly to Modulate Hydrogelation. Cringoli MC, Marchesan S. Molecules 28 4970 (2023)
  11. Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation. Chen Z, Ioris RM, Richardson S, Van Ess AN, Vendrell I, Kessler BM, Buffa FM, Busino L, Clifford SC, Bullock AN, D'Angiolella V. Cell Death Differ 29 1955-1969 (2022)
  12. Genome-wide identification and comprehensive analysis of tubby-like protein gene family in multiple crops. Zeng Y, Wen J, Fu J, Geng H, Dan Z, Zhao W, Xu W, Huang W. Front Plant Sci 13 1093944 (2022)
  13. 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 XQ. BMC Plant Biol 22 226 (2022)
  14. Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove. Cheng P, Hou Y, Bian M, Fang X, Liu Y, Rao Y, Cao S, Liu Y, Zhang S, Chen Y, Dong X, Liu Z. Commun Biol 6 1260 (2023)
  15. 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. Genes (Basel) 12 869 (2021)
  16. Structural basis for ubiquitylation by HOIL-1. Wu Q, Koliopoulos MG, Rittinger K, Stieglitz B. Front Mol Biosci 9 1098144 (2022)
  17. Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G. Kouno T, Shibata S, Shigematsu M, Hyun J, Kim TG, Matsuo H, Wolf M. Nat Commun 14 4037 (2023)
  18. 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, Yu Y, Liu L, Zhao M. Nature 600 334-338 (2021)
  19. Structure of CRL2Lrr1, the E3 ubiquitin ligase that promotes DNA replication termination in vertebrates. Zhou H, Zaher MS, Walter JC, Brown A. Nucleic Acids Res 49 13194-13206 (2021)
  20. Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation. Hopf LVM, Baek K, Klügel M, von Gronau S, Xiong Y, Schulman BA. Nat Struct Mol Biol 29 854-862 (2022)
  21. 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. Structure 31 541-552.e4 (2023)
  22. 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. Cell Death Dis 14 850 (2023)
  23. The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS. Xiong TC, Wei MC, Li FX, Shi M, Gan H, Tang Z, Dong HP, Liuyu T, Gao P, Zhong B, Zhang ZD, Lin D. Nat Commun 13 5973 (2022)
  24. The structural basis for HIV-1 Vif antagonism of human APOBEC3G. Li YL, Langley CA, Azumaya CM, Echeverria I, Chesarino NM, Emerman M, Cheng Y, Gross JD. Nature 615 728-733 (2023)


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