3rpg

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Bmi1/Ring1b-UbcH5c complex structureBmi1/Ring1b-UbcH5c complex structure

Structural highlights

3rpg is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:UBE2D3, UBC5C, UBCH5C (HUMAN), BMI1, PCGF4, RNF51 (HUMAN), RNF2, BAP1, DING, HIPI3, RING1B (HUMAN)
Activity:Ubiquitin--protein ligase, with EC number 6.3.2.19
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UB2D3_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-, as well as 'Lys-48'-linked polyubiquitination. Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. Acts also as an initiator E2, in conjunction with RNF8, for the priming of PCNA. Monoubiquitination of PCNA, and its subsequent polyubiquitination, are essential events in the operation of the DNA damage tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase. Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair. Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53. Supports NRDP1-mediated ubiquitination and degradation of ERBB3 and of BRUCE which triggers apoptosis. In conjunction with the CBL E3 ligase, targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization and transport on endosomes. In conjunction with the STUB1 E3 quality control E3 ligase, ubiquitinates unfolded proteins to catalyze their immediate destruction (By similarity).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [RING2_HUMAN] E3 ubiquitin-protein ligase that mediates monoubiquitination of 'Lys-119' of histone H2A, thereby playing a central role in histone code and gene regulation. H2A 'Lys-119' ubiquitination gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity.[15] [16] [17] [18] [19] [BMI1_HUMAN] Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. In the PRC1 complex, it is required to stimulate the E3 ubiquitin-protein ligase activity of RNF2/RING2.[20] [21] [22]

Publication Abstract from PubMed

The Polycomb repressive complex 1 (PRC1) mediates gene silencing, in part by monoubiquitination of histone H2A on lysine 119 (uH2A). Bmi1 and Ring1b are critical components of PRC1 that heterodimerize via their N-terminal RING domains to form an active E3 ubiquitin ligase. We have determined the crystal structure of a complex between the Bmi1/Ring1b RING-RING heterodimer and the E2 enzyme UbcH5c and find that UbcH5c interacts with Ring1b only, in a manner fairly typical of E2-E3 interactions. However, we further show that the Bmi1/Ring1b RING domains bind directly to duplex DNA through a basic surface patch unique to the Bmi1/Ring1b RING-RING dimer. Mutation of residues on this interaction surface leads to a loss of H2A ubiquitination activity. Computational modelling of the interface between Bmi1/Ring1b-UbcH5c and the nucleosome suggests that Bmi1/Ring1b interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve specific monoubiquitination of H2A. Our results point to a novel mechanism of substrate recognition, and control of product formation, by Bmi1/Ring1b.

Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex.,Bentley ML, Corn JE, Dong KC, Phung Q, Cheung TK, Cochran AG EMBO J. 2011 Jul 19. doi: 10.1038/emboj.2011.243. PMID:21772249[23]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Gonen H, Bercovich B, Orian A, Carrano A, Takizawa C, Yamanaka K, Pagano M, Iwai K, Ciechanover A. Identification of the ubiquitin carrier proteins, E2s, involved in signal-induced conjugation and subsequent degradation of IkappaBalpha. J Biol Chem. 1999 May 21;274(21):14823-30. PMID:10329681
  2. ↑ Murata S, Minami Y, Minami M, Chiba T, Tanaka K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2001 Dec;2(12):1133-8. Epub 2001 Nov 21. PMID:11743028 doi:http://dx.doi.org/10.1093/embo-reports/kve246
  3. ↑ Yogosawa S, Miyauchi Y, Honda R, Tanaka H, Yasuda H. Mammalian Numb is a target protein of Mdm2, ubiquitin ligase. Biochem Biophys Res Commun. 2003 Mar 21;302(4):869-72. PMID:12646252
  4. ↑ Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin EH. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem. 2004 Aug 27;279(35):36440-4. Epub 2004 Jul 9. PMID:15247280 doi:http://dx.doi.org/10.1074/jbc.C400300200
  5. ↑ Saville MK, Sparks A, Xirodimas DP, Wardrop J, Stevenson LF, Bourdon JC, Woods YL, Lane DP. Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J Biol Chem. 2004 Oct 1;279(40):42169-81. Epub 2004 Jul 26. PMID:15280377 doi:10.1074/jbc.M403362200
  6. ↑ Huang J, Huang Q, Zhou X, Shen MM, Yen A, Yu SX, Dong G, Qu K, Huang P, Anderson EM, Daniel-Issakani S, Buller RM, Payan DG, Lu HH. The poxvirus p28 virulence factor is an E3 ubiquitin ligase. J Biol Chem. 2004 Dec 24;279(52):54110-6. Epub 2004 Oct 20. PMID:15496420 doi:http://dx.doi.org/10.1074/jbc.M410583200
  7. ↑ Polanowska J, Martin JS, Garcia-Muse T, Petalcorin MI, Boulton SJ. A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J. 2006 May 17;25(10):2178-88. Epub 2006 Apr 20. PMID:16628214 doi:http://dx.doi.org/10.1038/sj.emboj.7601102
  8. ↑ Ohbayashi N, Okada K, Kawakami S, Togi S, Sato N, Ikeda O, Kamitani S, Muromoto R, Sekine Y, Kawai T, Akira S, Matsuda T. Physical and functional interactions between ZIP kinase and UbcH5. Biochem Biophys Res Commun. 2008 Aug 8;372(4):708-12. doi:, 10.1016/j.bbrc.2008.05.113. Epub 2008 Jun 2. PMID:18515077 doi:10.1016/j.bbrc.2008.05.113
  9. ↑ Zhang S, Chea J, Meng X, Zhou Y, Lee EY, Lee MY. PCNA is ubiquitinated by RNF8. Cell Cycle. 2008 Nov 1;7(21):3399-404. PMID:18948756
  10. ↑ Umebayashi K, Stenmark H, Yoshimori T. Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Mol Biol Cell. 2008 Aug;19(8):3454-62. doi: 10.1091/mbc.E07-10-0988. Epub 2008, May 28. PMID:18508924 doi:http://dx.doi.org/10.1091/mbc.E07-10-0988
  11. ↑ Kubori T, Hyakutake A, Nagai H. Legionella translocates an E3 ubiquitin ligase that has multiple U-boxes with distinct functions. Mol Microbiol. 2008 Mar;67(6):1307-19. doi: 10.1111/j.1365-2958.2008.06124.x., Epub 2008 Feb 13. PMID:18284575 doi:http://dx.doi.org/10.1111/j.1365-2958.2008.06124.x
  12. ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
  13. ↑ Wu K, Kovacev J, Pan ZQ. Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol Cell. 2010 Mar 26;37(6):784-96. doi: 10.1016/j.molcel.2010.02.025. PMID:20347421 doi:10.1016/j.molcel.2010.02.025
  14. ↑ Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature. 2011 Jun 2;474(7349):105-8. doi: 10.1038/nature09966. Epub 2011 May 1. PMID:21532592 doi:10.1038/nature09966
  15. ↑ Lee SJ, Choi JY, Sung YM, Park H, Rhim H, Kang S. E3 ligase activity of RING finger proteins that interact with Hip-2, a human ubiquitin-conjugating enzyme. FEBS Lett. 2001 Aug 10;503(1):61-4. PMID:11513855
  16. ↑ Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y. Role of histone H2A ubiquitination in Polycomb silencing. Nature. 2004 Oct 14;431(7010):873-8. Epub 2004 Sep 22. PMID:15386022 doi:10.1038/nature02985
  17. ↑ Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005 Dec 22;20(6):845-54. PMID:16359901 doi:10.1016/j.molcel.2005.12.002
  18. ↑ Li Z, Cao R, Wang M, Myers MP, Zhang Y, Xu RM. Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem. 2006 Jul 21;281(29):20643-9. Epub 2006 May 18. PMID:16714294 doi:10.1074/jbc.M602461200
  19. ↑ Wang R, Taylor AB, Leal BZ, Chadwell LV, Ilangovan U, Robinson AK, Schirf V, Hart PJ, Lafer EM, Demeler B, Hinck AP, McEwen DG, Kim CA. Polycomb group targeting through different binding partners of RING1B C-terminal domain. Structure. 2010 Aug 11;18(8):966-75. PMID:20696397 doi:10.1016/j.str.2010.04.013
  20. ↑ Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005 Dec 22;20(6):845-54. PMID:16359901 doi:10.1016/j.molcel.2005.12.002
  21. ↑ Chagraoui J, Niessen SL, Lessard J, Girard S, Coulombe P, Sauvageau M, Meloche S, Sauvageau G. E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 2006 Aug 1;20(15):2110-20. PMID:16882984 doi:http://dx.doi.org/20/15/2110
  22. ↑ Li Z, Cao R, Wang M, Myers MP, Zhang Y, Xu RM. Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem. 2006 Jul 21;281(29):20643-9. Epub 2006 May 18. PMID:16714294 doi:10.1074/jbc.M602461200
  23. ↑ Bentley ML, Corn JE, Dong KC, Phung Q, Cheung TK, Cochran AG. Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J. 2011 Jul 19. doi: 10.1038/emboj.2011.243. PMID:21772249 doi:10.1038/emboj.2011.243

3rpg, resolution 2.65Å

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