| Structural highlights
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]
Publication Abstract from PubMed
RING-type E3 ubiquitin ligases promote ubiquitylation by stabilising an active complex between a ubiquitin-loaded E2-conjugating enzyme and a protein substrate. To fulfil this function, the E3 ubiquitin-protein ligase SIAH1 and other SINA/SIAH subfamily RING-type E3 ligases employ an N-terminal catalytic RING domain and a C-terminal substrate-binding domain (SBD), separated by two zinc fingers. Here, we present the first crystal structure of the RING domain of human SIAH1, together with an adjacent zinc finger, revealing a potential RING dimer, which was validated in solution using static light scattering. RING dimerisation contributes to the E3 ligase activity of SIAH1 both in vitro and in cells. Moreover, as the RING domain is the second element, after the SBD, to independently favour homodimerisation within SINA/SIAH E3 ligases, we propose that alternating RING:RING and SBD:SBD interactions organise multiple copies of a SINA/SIAH protein into a higher-order homomultimer. In line with this hypothesis, fluorescently tagged full-length human SIAH1, human SIAH2 and fruit fly SINA show cytoplasmic clusters in human cells, whereas their distribution becomes more diffuse when RING dimerisation is disabled. The wild-type (WT) form of SIAH1, but not its RING dimerisation mutant, colocalises with aggregated synphilin-1A under proteasomal inhibition, suggesting that SIAH1 multimerisation might contribute to its reported preference for aggregated or multimeric substrates.
RING dimerisation drives higher-order organisation of SINA/SIAH E3 ubiquitin ligases.,Coste F, Mishra A, Chapuis C, Mance L, Pukalo Z, Bigot N, Goffinont S, Gaudon V, Garnier N, Talhaoui I, Castaing B, Huet S, Suskiewicz MJ FEBS J. 2025 Feb 5. doi: 10.1111/febs.70000. PMID:39910688[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Coste F, Mishra A, Chapuis C, Mance L, Pukało Z, Bigot N, Goffinont S, Gaudon V, Garnier N, Talhaoui I, Castaing B, Huet S, Suskiewicz MJ. RING dimerisation drives higher-order organisation of SINA/SIAH E3 ubiquitin ligases. FEBS J. 2025 Feb 5. PMID:39910688 doi:10.1111/febs.70000
|
