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Molecular basis for the association of human E4B U box ubiquitin ligase with E2-conjugating enzymes UbcH5c and Ubc4.

Benirschke RC, Thompson JR, Nominé Y, Wasielewski E, Juranić N, Macura S, Hatakeyama S, Nakayama KI, Botuyan MV, Mer G
Structure 18 955-65 (2010)
Related entries: 2kre, 3l1y, 3l1z

Cited: 32 times
EuropePMC logo PMID: 20696396

Abstract

Human E4B, also called UFD2a, is a U box-containing protein that functions as an E3 ubiquitin ligase and an E4 polyubiquitin chain elongation factor. E4B is thought to participate in the proteasomal degradation of misfolded or damaged proteins through association with chaperones. The U box domain is an anchor site for E2 ubiquitin-conjugating enzymes, but little is known of the binding mechanism. Using X-ray crystallography and NMR spectroscopy, we determined the structures of E4B U box free and bound to UbcH5c and Ubc4 E2s. Whereas previously characterized U box domains are homodimeric, we show that E4B U box is a monomer stabilized by a network of hydrogen bonds identified from scalar coupling measurements. These structural studies, complemented by calorimetry- and NMR-based binding assays, suggest an allosteric regulation of UbcH5c and Ubc4 by E4B U box and provide a molecular basis to understand how the ubiquitylation machinery involving E4B assembles.

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Reviews citing this publication (10)

  1. Ubiquitin Ligases: Structure, Function, and Regulation. Zheng N, Shabek N. Annu Rev Biochem 86 129-157 (2017)
  2. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Buetow L, Huang DT. Nat Rev Mol Cell Biol 17 626-642 (2016)
  3. Structural and functional insights to ubiquitin-like protein conjugation. Streich FC, Lima CD. Annu Rev Biophys 43 357-379 (2014)
  4. Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3. Alpi AF, Chaugule V, Walden H. Biochem J 473 3401-3419 (2016)
  5. Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond. Zhao B, Tsai YC, Jin B, Wang B, Wang Y, Zhou H, Carpenter T, Weissman AM, Yin J. Pharmacol Rev 72 380-413 (2020)
  6. Structural basis of generic versus specific E2-RING E3 interactions in protein ubiquitination. Gundogdu M, Walden H. Protein Sci 28 1758-1770 (2019)
  7. Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation. Márquez-Cantudo L, Ramos A, Coderch C, de Pascual-Teresa B. Molecules 26 5606 (2021)
  8. Ubiquitin-regulating effector proteins from Legionella. Jeong M, Jeon H, Shin D. BMB Rep 55 316-322 (2022)
  9. Ubiquitin-targeted bacterial effectors: rule breakers of the ubiquitin system. Roberts CG, Franklin TG, Pruneda JN. EMBO J 42 e114318 (2023)
  10. Targeted Protein Degradation: Principles and Applications of the Proteasome. Kim Y, Kim EK, Chey Y, Song MJ, Jang HH. Cells 12 1846 (2023)

Articles citing this publication (21)

  1. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Pruneda JN, Littlefield PJ, Soss SE, Nordquist KA, Chazin WJ, Brzovic PS, Klevit RE. Mol Cell 47 933-942 (2012)
  2. Activity-enhancing mutations in an E3 ubiquitin ligase identified by high-throughput mutagenesis. Starita LM, Pruneda JN, Lo RS, Fowler DM, Kim HJ, Hiatt JB, Shendure J, Brzovic PS, Fields S, Klevit RE. Proc Natl Acad Sci U S A 110 E1263-72 (2013)
  3. Activation of a primed RING E3-E2-ubiquitin complex by non-covalent ubiquitin. Buetow L, Gabrielsen M, Anthony NG, Dou H, Patel A, Aitkenhead H, Sibbet GJ, Smith BO, Huang DT. Mol Cell 58 297-310 (2015)
  4. Mechanisms of Ubiquitin-Nucleosome Recognition and Regulation of 53BP1 Chromatin Recruitment by RNF168/169 and RAD18. Hu Q, Botuyan MV, Cui G, Zhao D, Mer G. Mol Cell 66 473-487.e9 (2017)
  5. A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants. Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W, Sidhu SS, Huang DT. Mol Cell 68 456-470.e10 (2017)
  6. Activation of UbcH5c~Ub is the result of a shift in interdomain motions of the conjugate bound to U-box E3 ligase E4B. Soss SE, Klevit RE, Chazin WJ. Biochemistry 52 2991-2999 (2013)
  7. Changes in PUB22 Ubiquitination Modes Triggered by MITOGEN-ACTIVATED PROTEIN KINASE3 Dampen the Immune Response. Furlan G, Nakagami H, Eschen-Lippold L, Jiang X, Majovsky P, Kowarschik K, Hoehenwarter W, Lee J, Trujillo M. Plant Cell 29 726-745 (2017)
  8. Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation. Hu Q, Botuyan MV, Zhao D, Cui G, Mer E, Mer G. Nature 596 438-443 (2021)
  9. Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer. Bhuripanyo K, Wang Y, Liu X, Zhou L, Liu R, Duong D, Zhao B, Bi Y, Zhou H, Chen G, Seyfried NT, Chazin WJ, Kiyokawa H, Yin J. Sci Adv 4 e1701393 (2018)
  10. Molecular Characterization of LubX: Functional Divergence of the U-Box Fold by Legionella pneumophila. Quaile AT, Urbanus ML, Stogios PJ, Nocek B, Skarina T, Ensminger AW, Savchenko A. Structure 23 1459-1469 (2015)
  11. Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response. Walser F, Mulder MPC, Bragantini B, Burger S, Gubser T, Gatti M, Botuyan MV, Villa A, Altmeyer M, Neri D, Ovaa H, Mer G, Penengo L. Mol Cell 80 423-436.e9 (2020)
  12. The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97. Trusch F, Matena A, Vuk M, Koerver L, Knævelsrud H, Freemont PS, Meyer H, Bayer P. J Biol Chem 290 29414-29427 (2015)
  13. Tuning BRCA1 and BARD1 activity to investigate RING ubiquitin ligase mechanisms. Stewart MD, Duncan ED, Coronado E, DaRosa PA, Pruneda JN, Brzovic PS, Klevit RE. Protein Sci 26 475-483 (2017)
  14. The N-terminal tetra-peptide (IPDE) short extension of the U-box motif in rice SPL11 E3 is essential for the interaction with E2 and ubiquitin-ligase activity. Bae H, Kim WT. Biochem Biophys Res Commun 433 266-271 (2013)
  15. E3 ubiquitin-protein ligase TRIM21-mediated lysine capture by UBE2E1 reveals substrate-targeting mode of a ubiquitin-conjugating E2. Anandapadamanaban M, Kyriakidis NC, Csizmók V, Wallenhammar A, Espinosa AC, Ahlner A, Round AR, Trewhella J, Moche M, Wahren-Herlenius M, Sunnerhagen M. J Biol Chem 294 11404-11419 (2019)
  16. A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells. Mammen AL, Mahoney JA, St Germain A, Badders N, Taylor JP, Rosen A, Spinette S. PLoS One 6 e28861 (2011)
  17. TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs. Parnandi N, Rendo V, Cui G, Botuyan MV, Remisova M, Nguyen H, Drané P, Beroukhim R, Altmeyer M, Mer G, Chowdhury D. Mol Cell 81 2583-2595.e6 (2021)
  18. The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation. Mohanty S, Han T, Choi YB, Lavorgna A, Zhang J, Harhaj EW. PLoS Pathog 16 e1008504 (2020)
  19. A C2HC zinc finger is essential for the RING-E2 interaction of the ubiquitin ligase RNF125. Bijlmakers MJ, Teixeira JM, Boer R, Mayzel M, Puig-Sàrries P, Karlsson G, Coll M, Pons M, Crosas B. Sci Rep 6 29232 (2016)
  20. Further insights into the ubiquitin pathway: understanding the scarlet letter code. Pastore A. Structure 18 891-892 (2010)
  21. Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells. Osborne HC, Larrosa I, Schmidt CK. Int J Mol Sci 23 1116 (2022)


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