4x3g

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Crystal structure of SIAH1 SINA domain in complex with a USP19 peptideCrystal structure of SIAH1 SINA domain in complex with a USP19 peptide

Structural highlights

4x3g is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:Ubiquitinyl hydrolase 1, with EC number 3.4.19.12
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[SIAH1_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP. Confers constitutive instability to HIPK2 through proteasomal degradation. It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF-alpha signaling. Has some overlapping function with SIAH2. Induces apoptosis in cooperation with PEG3. Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus. GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [UBP19_HUMAN] Deubiquitinating enzyme that regulates the degradation of various proteins. Deubiquitinates and prevents proteasomal degradation of RNF123 which in turn stimulates CDKN1B ubiquitin-dependent degradation thereby playing a role in cell proliferation. Involved in decreased protein synthesis in atrophying skeletal muscle. Modulates transcription of major myofibrillar proteins. Also involved in turnover of endoplasmic-reticulum-associated degradation (ERAD) substrates. Regulates the stability of BIRC2/c-IAP1 and BIRC3/c-IAP2 by preventing their ubiquitination. Required for cells to mount an appropriate response to hypoxia and rescues HIF1A from degradation in a non-catalytic manner. Plays an important role in 17 beta-estradiol (E2)-inhibited myogenesis. Decreases the levels of ubiquitinated proteins during skeletal muscle formation and acts to repress myogenesis. Exhibits a preference towards 'Lys-63'-linked Ubiquitin chains.[20] [21] [22] [23]

References

  1. ↑ Hu G, Zhang S, Vidal M, Baer JL, Xu T, Fearon ER. Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway. Genes Dev. 1997 Oct 15;11(20):2701-14. PMID:9334332
  2. ↑ Hu G, Fearon ER. Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Mol Cell Biol. 1999 Jan;19(1):724-32. PMID:9858595
  3. ↑ Germani A, Bruzzoni-Giovanelli H, Fellous A, Gisselbrecht S, Varin-Blank N, Calvo F. SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis. Oncogene. 2000 Dec 7;19(52):5997-6006. PMID:11146551 doi:10.1038/sj.onc.1204002
  4. ↑ Tanikawa J, Ichikawa-Iwata E, Kanei-Ishii C, Nakai A, Matsuzawa S, Reed JC, Ishii S. p53 suppresses the c-Myb-induced activation of heat shock transcription factor 3. J Biol Chem. 2000 May 19;275(20):15578-85. PMID:10747903 doi:10.1074/jbc.M000372200
  5. ↑ Matsuzawa SI, Reed JC. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell. 2001 May;7(5):915-26. PMID:11389839
  6. ↑ Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL, White RL, Matsunami N. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell. 2001 May;7(5):927-36. PMID:11389840
  7. ↑ Tiedt R, Bartholdy BA, Matthias G, Newell JW, Matthias P. The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1. EMBO J. 2001 Aug 1;20(15):4143-52. PMID:11483517 doi:10.1093/emboj/20.15.4143
  8. ↑ Boehm J, He Y, Greiner A, Staudt L, Wirth T. Regulation of BOB.1/OBF.1 stability by SIAH. EMBO J. 2001 Aug 1;20(15):4153-62. PMID:11483518 doi:10.1093/emboj/20.15.4153
  9. ↑ Susini L, Passer BJ, Amzallag-Elbaz N, Juven-Gershon T, Prieur S, Privat N, Tuynder M, Gendron MC, Israel A, Amson R, Oren M, Telerman A. Siah-1 binds and regulates the function of Numb. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15067-72. PMID:11752454 doi:10.1073/pnas.261571998
  10. ↑ Johnsen SA, Subramaniam M, Monroe DG, Janknecht R, Spelsberg TC. Modulation of transforming growth factor beta (TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue. J Biol Chem. 2002 Aug 23;277(34):30754-9. Epub 2002 Jun 18. PMID:12072443 doi:10.1074/jbc.M204812200
  11. ↑ Nagano Y, Yamashita H, Takahashi T, Kishida S, Nakamura T, Iseki E, Hattori N, Mizuno Y, Kikuchi A, Matsumoto M. Siah-1 facilitates ubiquitination and degradation of synphilin-1. J Biol Chem. 2003 Dec 19;278(51):51504-14. Epub 2003 Sep 23. PMID:14506261 doi:10.1074/jbc.M306347200
  12. ↑ Germani A, Prabel A, Mourah S, Podgorniak MP, Di Carlo A, Ehrlich R, Gisselbrecht S, Varin-Blank N, Calvo F, Bruzzoni-Giovanelli H. SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway. Oncogene. 2003 Dec 4;22(55):8845-51. PMID:14654780 doi:10.1038/sj.onc.1206994
  13. ↑ Fanelli M, Fantozzi A, De Luca P, Caprodossi S, Matsuzawa S, Lazar MA, Pelicci PG, Minucci S. The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome. J Biol Chem. 2004 Feb 13;279(7):5374-9. Epub 2003 Nov 25. PMID:14645235 doi:10.1074/jbc.M306407200
  14. ↑ Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5500-5. Epub 2004 Apr 2. PMID:15064394 doi:10.1073/pnas.0401081101
  15. ↑ Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG. Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat Cell Biol. 2008 Jul;10(7):812-24. doi: 10.1038/ncb1743. Epub 2008 Jun 8. PMID:18536714 doi:10.1038/ncb1743
  16. ↑ Szargel R, Rott R, Eyal A, Haskin J, Shani V, Balan L, Wolosker H, Engelender S. Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation. J Biol Chem. 2009 Apr 24;284(17):11706-16. doi: 10.1074/jbc.M805990200. Epub 2009, Feb 17. PMID:19224863 doi:10.1074/jbc.M805990200
  17. ↑ Buchwald M, Pietschmann K, Muller JP, Bohmer FD, Heinzel T, Kramer OH. Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation. Leukemia. 2010 Aug;24(8):1412-21. doi: 10.1038/leu.2010.114. Epub 2010 May 27. PMID:20508617 doi:10.1038/leu.2010.114
  18. ↑ Liu M, Hsu J, Chan C, Li Z, Zhou Q. The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription. Mol Cell. 2012 May 11;46(3):325-34. doi: 10.1016/j.molcel.2012.03.007. Epub 2012 , Apr 5. PMID:22483617 doi:10.1016/j.molcel.2012.03.007
  19. ↑ Santelli E, Leone M, Li C, Fukushima T, Preece NE, Olson AJ, Ely KR, Reed JC, Pellecchia M, Liddington RC, Matsuzawa S. Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex. J Biol Chem. 2005 Oct 7;280(40):34278-87. Epub 2005 Aug 4. PMID:16085652 doi:10.1074/jbc.M506707200
  20. ↑ Hassink GC, Zhao B, Sompallae R, Altun M, Gastaldello S, Zinin NV, Masucci MG, Lindsten K. The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep. 2009 Jul;10(7):755-61. Epub 2009 May 22. PMID:19465887 doi:http://dx.doi.org/embor200969
  21. ↑ Mei Y, Hahn AA, Hu S, Yang X. The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. J Biol Chem. 2011 Oct 14;286(41):35380-7. doi: 10.1074/jbc.M111.282020. Epub 2011, Aug 17. PMID:21849505 doi:http://dx.doi.org/10.1074/jbc.M111.282020
  22. ↑ Altun M, Zhao B, Velasco K, Liu H, Hassink G, Paschke J, Pereira T, Lindsten K. Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1alpha (HIF-1alpha) during hypoxia. J Biol Chem. 2012 Jan 13;287(3):1962-9. doi: 10.1074/jbc.M111.305615. Epub 2011, Nov 29. PMID:22128162 doi:http://dx.doi.org/10.1074/jbc.M111.305615
  23. ↑ Iphofer A, Kummer A, Nimtz M, Ritter A, Arnold T, Frank R, van den Heuvel J, Kessler BM, Jansch L, Franke R. Profiling ubiquitin linkage specificities of deubiquitinating enzymes with branched ubiquitin isopeptide probes. Chembiochem. 2012 Jul 9;13(10):1416-20. doi: 10.1002/cbic.201200261. Epub 2012, Jun 11. PMID:22689415 doi:10.1002/cbic.201200261

4x3g, resolution 2.34Å

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