ID SIAH1_HUMAN Reviewed; 282 AA. AC Q8IUQ4; A0FKF3; O43269; Q49A58; Q92880; DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 26-APR-2004, sequence version 2. DT 10-JUN-2026, entry version 213. DE RecName: Full=E3 ubiquitin-protein ligase SIAH1; DE EC=2.3.2.27 {ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:28546513}; DE AltName: Full=RING-type E3 ubiquitin transferase SIAH1 {ECO:0000305}; DE AltName: Full=Seven in absentia homolog 1; DE Short=Siah-1; DE AltName: Full=Siah-1a; GN Name=SIAH1; Synonyms=HUMSIAH; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Intestinal epithelium; RX PubMed=8799150; DOI=10.1073/pnas.93.17.9039; RA Nemani M., Linares-Cruz G., Bruzzoni-Giovanelli H., Roperch J.-P., RA Tuynder M., Bougueleret L., Cherif D., Medhioub M., Pasturaud P., RA Alvaro V., Der Sarkissan H., Cazes L., Le Paslier D., Le Gall I., RA Israeli D., Dausset J., Sigaux F., Chumakov I., Oren M., Calvo F., RA Amson R.B., Cohen D., Telerman A.; RT "Activation of the human homologue of the Drosophila sina gene in apoptosis RT and tumor suppression."; RL Proc. Natl. Acad. Sci. U.S.A. 93:9039-9042(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=9403064; DOI=10.1006/geno.1997.4997; RA Hu G., Chung Y.-L., Glover T., Valentine V., Look A.T., Fearon E.R.; RT "Characterization of human homologs of the Drosophila seven in absentia RT (sina) gene."; RL Genomics 46:103-111(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10956387; RX DOI=10.1002/1097-0215(20000915)87:6<794::aid-ijc5>3.3.co;2-2; RA Medhioub M., Vaury C., Hamelin R., Thomas G.; RT "Lack of somatic mutation in the coding sequence of SIAH1 in tumors RT hemizygous for this candidate tumor suppressor gene."; RL Int. J. Cancer 87:794-797(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RX PubMed=17420721; DOI=10.1038/sj.onc.1210449; RA Mei Y., Xie C., Xie W., Wu Z., Wu M.; RT "Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), RT counteracts Siah-1-mediated downregulation of beta-catenin."; RL Oncogene 26:6319-6331(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Retina; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain, Pancreas, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP FUNCTION IN DEGRADATION OF DCC, SUBCELLULAR LOCATION, AND INTERACTION WITH RP UBE2I AND DCC. RX PubMed=9334332; DOI=10.1101/gad.11.20.2701; RA Hu G., Zhang S., Vidal M., Baer J.L., Xu T., Fearon E.R.; RT "Mammalian homologs of seven in absentia regulate DCC via the ubiquitin- RT proteasome pathway."; RL Genes Dev. 11:2701-2714(1997). RN [8] RP INTERACTION WITH BAG1, AND SUBCELLULAR LOCATION. RX PubMed=9582267; DOI=10.1093/emboj/17.10.2736; RA Matsuzawa S., Takayama S., Froesch B.A., Zapata J.M., Reed J.C.; RT "p53-inducible human homologue of Drosophila seven in absentia (Siah) RT inhibits cell growth: suppression by BAG-1."; RL EMBO J. 17:2736-2747(1998). RN [9] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-40; CYS-41; CYS-44; RP CYS-55; HIS-59; ARG-66; LYS-68; ARG-76; HIS-152; HIS-202 AND LEU-211. RX PubMed=9858595; DOI=10.1128/mcb.19.1.724; RA Hu G., Fearon E.R.; RT "Siah-1 N-terminal RING domain is required for proteolysis function, and C- RT terminal sequences regulate oligomerization and binding to target RT proteins."; RL Mol. Cell. Biol. 19:724-732(1999). RN [10] RP FUNCTION IN DEGRADATION OF KIF22, AND INTERACTION WITH ALPHA-TUBULIN. RX PubMed=11146551; DOI=10.1038/sj.onc.1204002; RA Germani A., Bruzzoni-Giovanelli H., Fellous A., Gisselbrecht S., RA Varin-Blank N., Calvo F.; RT "SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the RT proteasome pathway during mitosis."; RL Oncogene 19:5997-6006(2000). RN [11] RP FUNCTION IN DEGRADATION OF MYB. RX PubMed=10747903; DOI=10.1074/jbc.m000372200; RA Tanikawa J., Ichikawa-Iwata E., Kanei-Ishii C., Nakai A., Matsuzawa S., RA Reed J.C., Ishii S.; RT "p53 suppresses the c-Myb-induced activation of heat shock transcription RT factor 3."; RL J. Biol. Chem. 275:15578-15585(2000). RN [12] RP FUNCTION IN DEGRADATION OF CTNNB1, AND SUBUNIT OF A COMPLEX WITH UBE2D1; RP CACYBP; SKP1; APC AND TBL1X. RX PubMed=11389839; DOI=10.1016/s1097-2765(01)00242-8; RA Matsuzawa S., Reed J.C.; RT "Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin RT degradation linked to p53 responses."; RL Mol. Cell 7:915-926(2001). RN [13] RP FUNCTION IN DEGRADATION OF CTNNB1. RX PubMed=11389840; DOI=10.1016/s1097-2765(01)00241-6; RA Liu J., Stevens J., Rote C.A., Yost H.J., Hu Y., Neufeld K.L., White R.L., RA Matsunami N.; RT "Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to RT the adenomatous polyposis coli protein."; RL Mol. Cell 7:927-936(2001). RN [14] RP FUNCTION IN DEGRADATION OF POU2AF1, AND SUBCELLULAR LOCATION. RX PubMed=11483517; DOI=10.1093/emboj/20.15.4143; RA Tiedt R., Bartholdy B.A., Matthias G., Newell J.W., Matthias P.; RT "The RING finger protein Siah-1 regulates the level of the transcriptional RT coactivator OBF-1."; RL EMBO J. 20:4143-4152(2001). RN [15] RP FUNCTION IN DEGRADATION OF POU2AF1. RX PubMed=11483518; DOI=10.1093/emboj/20.15.4153; RA Boehm J., He Y., Greiner A., Staudt L., Wirth T.; RT "Regulation of BOB.1/OBF.1 stability by SIAH."; RL EMBO J. 20:4153-4162(2001). RN [16] RP FUNCTION IN DEGRADATION OF NUMB. RX PubMed=11752454; DOI=10.1073/pnas.261571998; RA Susini L., Passer B.J., Amzallag-Elbaz N., Juven-Gershon T., Prieur S., RA Privat N., Tuynder M., Gendron M.-C., Israeel A., Amson R., Oren M., RA Telerman A.; RT "Siah-1 binds and regulates the function of Numb."; RL Proc. Natl. Acad. Sci. U.S.A. 98:15067-15072(2001). RN [17] RP FUNCTION IN DEGRADATION OF KLF10. RX PubMed=12072443; DOI=10.1074/jbc.m204812200; RA Johnsen S.A., Subramaniam M., Monroe D.G., Janknecht R., Spelsberg T.C.; RT "Modulation of transforming growth factor beta (TGFbeta)/Smad RT transcriptional responses through targeted degradation of TGFbeta-inducible RT early gene-1 by human seven in absentia homologue."; RL J. Biol. Chem. 277:30754-30759(2002). RN [18] RP FUNCTION IN DEGRADATION OF SNCAIP, AND SUBCELLULAR LOCATION. RX PubMed=14506261; DOI=10.1074/jbc.m306347200; RA Nagano Y., Yamashita H., Takahashi T., Kishida S., Nakamura T., Iseki E., RA Hattori N., Mizuno Y., Kikuchi A., Matsumoto M.; RT "Siah-1 facilitates ubiquitination and degradation of synphilin-1."; RL J. Biol. Chem. 278:51504-51514(2003). RN [19] RP INTERACTION WITH PEG10. RX PubMed=12810624; RA Okabe H., Satoh S., Furukawa Y., Kato T., Hasegawa S., Nakajima Y., RA Yamaoka Y., Nakamura Y.; RT "Involvement of PEG10 in human hepatocellular carcinogenesis through RT interaction with SIAH1."; RL Cancer Res. 63:3043-3048(2003). RN [20] RP TISSUE SPECIFICITY. RX PubMed=12557228; DOI=10.1002/gcc.10170; RA Matsuo K., Satoh S., Okabe H., Nomura A., Maeda T., Yamaoka Y., Ikai I.; RT "SIAH1 inactivation correlates with tumor progression in hepatocellular RT carcinomas."; RL Genes Chromosomes Cancer 36:283-291(2003). RN [21] RP FUNCTION IN DEGRADATION OF RBBP8. RX PubMed=14654780; DOI=10.1038/sj.onc.1206994; RA Germani A., Prabel A., Mourah S., Podgorniak M.-P., Di Carlo A., RA Ehrlich R., Gisselbrecht S., Varin-Blank N., Calvo F., RA Bruzzoni-Giovanelli H.; RT "SIAH-1 interacts with CtIP and promotes its degradation by the proteasome RT pathway."; RL Oncogene 22:8845-8851(2003). RN [22] RP INTERACTION WITH CACYBP, MUTANTS A; B; C; D AND E, AND MUTAGENESIS OF RP ARG-124; ASP-142; GLN-151; ARG-224; GLU-226; ARG-233; GLU-237; ASN-253 AND RP GLN-265. RX PubMed=12421809; DOI=10.1074/jbc.m210263200; RA Matsuzawa S., Li C., Ni C.-Z., Takayama S., Reed J.C., Ely K.R.; RT "Structural analysis of Siah1 and its interactions with Siah-interacting RT protein (SIP)."; RL J. Biol. Chem. 278:1837-1840(2003). RN [23] RP INTERACTION WITH KHDRBS3. RX PubMed=15163637; DOI=10.1093/hmg/ddh165; RA Venables J.P., Dalgliesh C., Paronetto M.P., Skitt L., Thornton J.K., RA Saunders P.T., Sette C., Jones K.T., Elliott D.J.; RT "SIAH1 targets the alternative splicing factor T-STAR for degradation by RT the proteasome."; RL Hum. Mol. Genet. 13:1525-1534(2004). RN [24] RP FUNCTION IN DEGRADATION OF PML, AND MUTANTS A AND D. RX PubMed=14645235; DOI=10.1074/jbc.m306407200; RA Fanelli M., Fantozzi A., De Luca P., Caprodossi S., Matsuzawa S., RA Lazar M.A., Pelicci P.G., Minucci S.; RT "The coiled-coil domain is the structural determinant for mammalian RT homologues of Drosophila Sina-mediated degradation of promyelocytic RT leukemia protein and other tripartite motif proteins by the proteasome."; RL J. Biol. Chem. 279:5374-5379(2004). RN [25] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SNCAIP AND SNCA, AND RP MUTAGENESIS OF CYS-55; HIS-59 AND CYS-72. RX PubMed=15064394; DOI=10.1073/pnas.0401081101; RA Liani E., Eyal A., Avraham E., Shemer R., Szargel R., Berg D., RA Bornemann A., Riess O., Ross C.A., Rott R., Engelender S.; RT "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence RT in cellular inclusions and Lewy bodies imply a role in Parkinson's RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 101:5500-5505(2004). RN [26] RP FUNCTION, MUTAGENESIS OF SER-19 AND CYS-44, INTERACTION WITH HIPK2, AND RP PHOSPHORYLATION AT SER-19 BY ATM AND ATR. RX PubMed=18536714; DOI=10.1038/ncb1743; RA Winter M., Sombroek D., Dauth I., Moehlenbrink J., Scheuermann K., RA Crone J., Hofmann T.G.; RT "Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint RT kinases ATM and ATR."; RL Nat. Cell Biol. 10:812-824(2008). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [28] RP INTERACTION WITH SNCAIP, CATALYTIC ACTIVITY, ACTIVITY REGULATION, FUNCTION, RP AND PATHWAY. RX PubMed=19224863; DOI=10.1074/jbc.m805990200; RA Szargel R., Rott R., Eyal A., Haskin J., Shani V., Balan L., Wolosker H., RA Engelender S.; RT "Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates RT alpha-synuclein monoubiquitylation and inclusion formation."; RL J. Biol. Chem. 284:11706-11716(2009). RN [29] RP FUNCTION IN UBIQUITINATION OF FLT3. RX PubMed=20508617; DOI=10.1038/leu.2010.114; RA Buchwald M., Pietschmann K., Muller J.P., Bohmer F.D., Heinzel T., RA Kramer O.H.; RT "Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for RT proteasomal degradation."; RL Leukemia 24:1412-1421(2010). RN [30] RP FUNCTION. RX PubMed=22483617; DOI=10.1016/j.molcel.2012.03.007; RA Liu M., Hsu J., Chan C., Li Z., Zhou Q.; RT "The ubiquitin ligase Siah1 controls ELL2 stability and formation of super RT elongation complexes to modulate gene transcription."; RL Mol. Cell 46:325-334(2012). RN [31] RP FUNCTION, AND INTERACTION WITH DAZAP2 AND HIPK2. RX PubMed=33591310; DOI=10.1093/nar/gkab084; RA Liebl M.C., Moehlenbrink J., Becker H., Raddatz G., Abdeen S.K., RA Aqeilan R.I., Lyko F., Hofmann T.G.; RT "DAZAP2 acts as specifier of the p53 response to DNA damage."; RL Nucleic Acids Res. 49:2759-2776(2021). RN [32] {ECO:0007744|PDB:2A25} RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 90-282 IN COMPLEX WITH ZINC IONS RP AND CACYBP, FUNCTION, MUTAGENESIS OF 198-LYS--ASP-200 AND MET-252, AND RP INTERACTION WITH CACYBP. RX PubMed=16085652; DOI=10.1074/jbc.m506707200; RA Santelli E., Leone M., Li C., Fukushima T., Preece N.E., Olson A.J., RA Ely K.R., Reed J.C., Pellecchia M., Liddington R.C., Matsuzawa S.; RT "Structural analysis of Siah1-Siah-interacting protein interactions and RT insights into the assembly of an E3 ligase multiprotein complex."; RL J. Biol. Chem. 280:34278-34287(2005). RN [33] {ECO:0007744|PDB:5WZZ} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 93-282 IN COMPLEX WITH ZINC IONS RP AND AXIN1, INTERACTION WITH AXIN1, FUNCTION, CATALYTIC ACTIVITY, AND RP PATHWAY. RX PubMed=28546513; DOI=10.1101/gad.300053.117; RA Ji L., Jiang B., Jiang X., Charlat O., Chen A., Mickanin C., Bauer A., RA Xu W., Yan X., Cong F.; RT "The SIAH E3 ubiquitin ligases promote Wnt/beta-catenin signaling through RT mediating Wnt-induced Axin degradation."; RL Genes Dev. 31:904-915(2017). RN [34] RP VARIANTS BURHAS GLY-41; LEU-50; PHE-128; ALA-168 AND ARG-174, RP CHARACTERIZATION OF VARIANTS BURHAS GLY-41; LEU-50; PHE-128; ALA-168 AND RP ARG-174, AND FUNCTION. RX PubMed=32430360; DOI=10.1136/jmedgenet-2019-106335; RA Buratti J., Ji L., Keren B., Lee Y., Booke S., Erdin S., Kim S.Y., RA Palculict T.B., Meiner V., Chae J.H., Woods C.G., Tam A., Heron D., RA Cong F., Harel T.; RT "De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated RT with developmental delay, hypotonia and dysmorphic features."; RL J. Med. Genet. 58:205-212(2021). CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and CC subsequent proteasomal degradation of target proteins (PubMed:14506261, CC PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, CC PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:28546513, CC PubMed:32430360, PubMed:33591310, PubMed:9334332, PubMed:9858595). E3 CC ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating CC enzyme in the form of a thioester and then directly transfers the CC ubiquitin to targeted substrates (PubMed:14506261, PubMed:14645235, CC PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, CC PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). CC Mediates E3 ubiquitin ligase activity either through direct binding to CC substrates or by functioning as the essential RING domain subunit of CC larger E3 complexes (PubMed:14506261, PubMed:14645235, PubMed:14654780, CC PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, CC PubMed:22483617, PubMed:9334332, PubMed:9858595). Triggers the CC ubiquitin-mediated degradation of many substrates, including proteins CC involved in transcription regulation (ELL2, MYB, POU2AF1, PML and CC RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type CC tyrosine kinase FLT3, the cytoplasmic signal transduction molecules CC (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule CC motor protein (KIF22), a protein involved in synaptic vesicle function CC in neurons (SYP), a structural protein (CTNNB1) and SNCAIP CC (PubMed:10747903, PubMed:11146551, PubMed:11389839, PubMed:11389840, CC PubMed:11483517, PubMed:11483518, PubMed:11752454, PubMed:12072443). CC Confers constitutive instability to HIPK2 through proteasomal CC degradation (PubMed:18536714, PubMed:33591310). It is thereby involved CC in many cellular processes such as apoptosis, tumor suppression, cell CC cycle, axon guidance, transcription regulation, spermatogenesis and TNF CC signaling (PubMed:14506261, PubMed:14645235, PubMed:14654780, CC PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, CC PubMed:22483617, PubMed:9334332, PubMed:9858595). Has some overlapping CC function with SIAH2 (PubMed:14506261, PubMed:14645235, PubMed:14654780, CC PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, CC PubMed:22483617, PubMed:9334332, PubMed:9858595). Induces apoptosis in CC cooperation with PEG3 (By similarity). Upon nitric oxid (NO) generation CC that follows apoptotic stimulation, interacts with S-nitrosylated CC GAPDH, mediating the translocation of GAPDH to the nucleus (By CC similarity). GAPDH acts as a stabilizer of SIAH1, facilitating the CC degradation of nuclear proteins (By similarity). Mediates CC ubiquitination and degradation of EGLN2 and EGLN3 in response to the CC unfolded protein response (UPR), leading to their degradation and CC subsequent stabilization of ATF4 (By similarity). Also part of the Wnt CC signaling pathway in which it mediates the Wnt-induced ubiquitin- CC mediated proteasomal degradation of AXIN1 (PubMed:28546513, CC PubMed:32430360). {ECO:0000250|UniProtKB:P61092, CC ECO:0000250|UniProtKB:Q920M9, ECO:0000269|PubMed:10747903, CC ECO:0000269|PubMed:11146551, ECO:0000269|PubMed:11389839, CC ECO:0000269|PubMed:11389840, ECO:0000269|PubMed:11483517, CC ECO:0000269|PubMed:11483518, ECO:0000269|PubMed:11752454, CC ECO:0000269|PubMed:12072443, ECO:0000269|PubMed:14506261, CC ECO:0000269|PubMed:14645235, ECO:0000269|PubMed:14654780, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16085652, CC ECO:0000269|PubMed:18536714, ECO:0000269|PubMed:19224863, CC ECO:0000269|PubMed:20508617, ECO:0000269|PubMed:22483617, CC ECO:0000269|PubMed:28546513, ECO:0000269|PubMed:32430360, CC ECO:0000269|PubMed:9334332, ECO:0000269|PubMed:9858595}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:19224863, CC ECO:0000269|PubMed:28546513}; CC -!- ACTIVITY REGULATION: Inhibited by interaction with SNCAIP (isoform 2, CC but not isoform 1). May be inhibited by interaction with PEG10. CC {ECO:0000269|PubMed:19224863}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:28546513}. CC -!- SUBUNIT: Homodimer. Interacts with group 1 glutamate receptors GRM1 and CC GRM5. Interacts with DAB1, which may inhibit its activity. Interacts CC with UBE2E2. Interacts with PEG3. Interacts with GAPDH; leading to CC stabilize SIAH1 (By similarity). Component of some large E3 complex CC composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts CC with UBE2I. Interacts with alpha-tubulin. Interacts with PEG10, which CC may inhibit its activity. Interacts with KHDRBS3. Interacts with CC SNCAIP. Interacts with HIPK2; the interaction is promoted by DAZAP2 and CC results in SIAH1-mediated ubiquitination and subsequent proteasomal CC degradation of HIPK2 (PubMed:33591310). Interacts with DAZAP2; the CC interaction is decreased following phosphorylation of DAZAP2 by HIPK2 CC (PubMed:33591310). Interacts with Bassoon/BSN and Piccolo/PLCO; these CC interactions negatively regulate SIAH1 E3 ligase activity (By CC similarity). Interacts with DCC (PubMed:9334332). Interacts with AXIN1; CC catalyzes AXIN1 ubiquitination and subsequent proteasome-mediated CC ubiquitin-dependent degradation (PubMed:28546513). CC {ECO:0000250|UniProtKB:P61092, ECO:0000250|UniProtKB:Q920M9, CC ECO:0000269|PubMed:11146551, ECO:0000269|PubMed:11389839, CC ECO:0000269|PubMed:12421809, ECO:0000269|PubMed:12810624, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:15163637, CC ECO:0000269|PubMed:16085652, ECO:0000269|PubMed:18536714, CC ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:33591310, CC ECO:0000269|PubMed:9334332, ECO:0000269|PubMed:9582267}. CC -!- INTERACTION: CC Q8IUQ4; Q9NRN7: AASDHPPT; NbExp=3; IntAct=EBI-747107, EBI-740884; CC Q8IUQ4; Q9UHB7: AFF4; NbExp=5; IntAct=EBI-747107, EBI-395282; CC Q8IUQ4; Q9UHB7-2: AFF4; NbExp=5; IntAct=EBI-747107, EBI-10261324; CC Q8IUQ4; P29972: AQP1; NbExp=3; IntAct=EBI-747107, EBI-745213; CC Q8IUQ4; Q7Z3E5-2: ARMC9; NbExp=3; IntAct=EBI-747107, EBI-10256990; CC Q8IUQ4; O15265: ATXN7; NbExp=2; IntAct=EBI-747107, EBI-708350; CC Q8IUQ4; P41182: BCL6; NbExp=3; IntAct=EBI-747107, EBI-765407; CC Q8IUQ4; P40121: CAPG; NbExp=3; IntAct=EBI-747107, EBI-4291044; CC Q8IUQ4; Q9NVL8: CCDC198; NbExp=3; IntAct=EBI-747107, EBI-10238351; CC Q8IUQ4; Q9UJX2: CDC23; NbExp=3; IntAct=EBI-747107, EBI-396137; CC Q8IUQ4; P49427: CDC34; NbExp=3; IntAct=EBI-747107, EBI-975634; CC Q8IUQ4; Q8N619: CDK5R1; NbExp=3; IntAct=EBI-747107, EBI-10266998; CC Q8IUQ4; Q8TAM4: CDK5R1; NbExp=3; IntAct=EBI-747107, EBI-10271838; CC Q8IUQ4; Q9UJV9: DDX41; NbExp=3; IntAct=EBI-747107, EBI-1046350; CC Q8IUQ4; Q9Y5T4: DNAJC15; NbExp=3; IntAct=EBI-747107, EBI-10329228; CC Q8IUQ4; O14645: DNALI1; NbExp=3; IntAct=EBI-747107, EBI-395638; CC Q8IUQ4; P29692: EEF1D; NbExp=4; IntAct=EBI-747107, EBI-358607; CC Q8IUQ4; Q8N2X6: EXOC3-AS1; NbExp=3; IntAct=EBI-747107, EBI-749333; CC Q8IUQ4; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-747107, EBI-6658203; CC Q8IUQ4; Q01543: FLI1; NbExp=3; IntAct=EBI-747107, EBI-2271018; CC Q8IUQ4; Q8TAN2: FZD9; NbExp=3; IntAct=EBI-747107, EBI-741016; CC Q8IUQ4; Q8WTR4: GDPD5; NbExp=3; IntAct=EBI-747107, EBI-2833203; CC Q8IUQ4; P62805: H4C9; NbExp=3; IntAct=EBI-747107, EBI-302023; CC Q8IUQ4; P05111: INHA; NbExp=3; IntAct=EBI-747107, EBI-10194422; CC Q8IUQ4; Q9H0B3: IQCN; NbExp=3; IntAct=EBI-747107, EBI-745878; CC Q8IUQ4; Q9BW62: KATNAL1; NbExp=3; IntAct=EBI-747107, EBI-743591; CC Q8IUQ4; P78508: KCNJ10; NbExp=3; IntAct=EBI-747107, EBI-9117877; CC Q8IUQ4; Q8IZA0: KIAA0319L; NbExp=3; IntAct=EBI-747107, EBI-5240269; CC Q8IUQ4; Q5T5P2-6: KIAA1217; NbExp=3; IntAct=EBI-747107, EBI-10188326; CC Q8IUQ4; O60333: KIF1B; NbExp=3; IntAct=EBI-747107, EBI-465633; CC Q8IUQ4; Q9BVG8: KIFC3; NbExp=3; IntAct=EBI-747107, EBI-2125614; CC Q8IUQ4; Q53H82: LACTB2; NbExp=3; IntAct=EBI-747107, EBI-3943430; CC Q8IUQ4; Q13394: MAB21L1; NbExp=3; IntAct=EBI-747107, EBI-10229059; CC Q8IUQ4; P53778: MAPK12; NbExp=3; IntAct=EBI-747107, EBI-602406; CC Q8IUQ4; O60336: MAPKBP1; NbExp=3; IntAct=EBI-747107, EBI-947402; CC Q8IUQ4; Q70IA8: MOB3C; NbExp=3; IntAct=EBI-747107, EBI-9679267; CC Q8IUQ4; Q9H2K0: MTIF3; NbExp=3; IntAct=EBI-747107, EBI-3923617; CC Q8IUQ4; P20591: MX1; NbExp=3; IntAct=EBI-747107, EBI-929476; CC Q8IUQ4; Q99836: MYD88; NbExp=3; IntAct=EBI-747107, EBI-447677; CC Q8IUQ4; Q92692: NECTIN2; NbExp=3; IntAct=EBI-747107, EBI-718419; CC Q8IUQ4; Q9H3P2: NELFA; NbExp=3; IntAct=EBI-747107, EBI-5461341; CC Q8IUQ4; Q9H6R4-4: NOL6; NbExp=3; IntAct=EBI-747107, EBI-10307896; CC Q8IUQ4; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-747107, EBI-741158; CC Q8IUQ4; P35372: OPRM1; NbExp=4; IntAct=EBI-747107, EBI-2624570; CC Q8IUQ4; Q96DC9: OTUB2; NbExp=3; IntAct=EBI-747107, EBI-746259; CC Q8IUQ4; Q86TG7: PEG10; NbExp=3; IntAct=EBI-747107, EBI-2858265; CC Q8IUQ4; P08237: PFKM; NbExp=3; IntAct=EBI-747107, EBI-514788; CC Q8IUQ4; Q8IXK0: PHC2; NbExp=5; IntAct=EBI-747107, EBI-713786; CC Q8IUQ4; Q16633: POU2AF1; NbExp=2; IntAct=EBI-747107, EBI-943588; CC Q8IUQ4; Q8WWY3: PRPF31; NbExp=3; IntAct=EBI-747107, EBI-1567797; CC Q8IUQ4; P86479: PRR20C; NbExp=5; IntAct=EBI-747107, EBI-10172814; CC Q8IUQ4; Q8WUK0: PTPMT1; NbExp=3; IntAct=EBI-747107, EBI-7199479; CC Q8IUQ4; Q9UHX1: PUF60; NbExp=7; IntAct=EBI-747107, EBI-1053259; CC Q8IUQ4; P11216: PYGB; NbExp=3; IntAct=EBI-747107, EBI-1047231; CC Q8IUQ4; Q2TAL8: QRICH1; NbExp=3; IntAct=EBI-747107, EBI-2798044; CC Q8IUQ4; Q14088: RAB33A; NbExp=3; IntAct=EBI-747107, EBI-744685; CC Q8IUQ4; Q96B01: RAD51AP1; NbExp=3; IntAct=EBI-747107, EBI-1178724; CC Q8IUQ4; Q96B01-2: RAD51AP1; NbExp=3; IntAct=EBI-747107, EBI-1178743; CC Q8IUQ4; Q9Y4B4: RAD54L2; NbExp=3; IntAct=EBI-747107, EBI-948156; CC Q8IUQ4; Q86WX3: RPS19BP1; NbExp=3; IntAct=EBI-747107, EBI-4479407; CC Q8IUQ4; O00560: SDCBP; NbExp=3; IntAct=EBI-747107, EBI-727004; CC Q8IUQ4; O43236-6: SEPTIN4; NbExp=2; IntAct=EBI-747107, EBI-4372019; CC Q8IUQ4; Q8IUQ4: SIAH1; NbExp=3; IntAct=EBI-747107, EBI-747107; CC Q8IUQ4; Q8NEY3: SPATA4; NbExp=3; IntAct=EBI-747107, EBI-7067221; CC Q8IUQ4; Q9H0A9: SPATC1L; NbExp=3; IntAct=EBI-747107, EBI-372911; CC Q8IUQ4; O43581: SYT7; NbExp=3; IntAct=EBI-747107, EBI-10184345; CC Q8IUQ4; Q9NU19: TBC1D22B; NbExp=3; IntAct=EBI-747107, EBI-8787464; CC Q8IUQ4; Q9BTV4: TMEM43; NbExp=3; IntAct=EBI-747107, EBI-721293; CC Q8IUQ4; Q6FIE9: TOLLIP; NbExp=3; IntAct=EBI-747107, EBI-10249783; CC Q8IUQ4; Q13625-3: TP53BP2; NbExp=3; IntAct=EBI-747107, EBI-10175039; CC Q8IUQ4; P36406: TRIM23; NbExp=3; IntAct=EBI-747107, EBI-740098; CC Q8IUQ4; P14373: TRIM27; NbExp=3; IntAct=EBI-747107, EBI-719493; CC Q8IUQ4; Q9C029: TRIM7; NbExp=3; IntAct=EBI-747107, EBI-2813981; CC Q8IUQ4; P61086: UBE2K; NbExp=4; IntAct=EBI-747107, EBI-473850; CC Q8IUQ4; O95045: UPP2; NbExp=3; IntAct=EBI-747107, EBI-10191025; CC Q8IUQ4; Q9UBK9: UXT; NbExp=3; IntAct=EBI-747107, EBI-357355; CC Q8IUQ4; P98170: XIAP; NbExp=3; IntAct=EBI-747107, EBI-517127; CC Q8IUQ4; A2RRL9: ZBP1; NbExp=3; IntAct=EBI-747107, EBI-10173066; CC Q8IUQ4; Q8TBK6: ZCCHC10; NbExp=3; IntAct=EBI-747107, EBI-597063; CC Q8IUQ4; Q8WW36: ZCCHC13; NbExp=3; IntAct=EBI-747107, EBI-954111; CC Q8IUQ4; Q9BQ24: ZFYVE21; NbExp=3; IntAct=EBI-747107, EBI-2849569; CC Q8IUQ4; Q9HA38: ZMAT3; NbExp=3; IntAct=EBI-747107, EBI-2548480; CC Q8IUQ4; Q9UQR1: ZNF148; NbExp=3; IntAct=EBI-747107, EBI-2688184; CC Q8IUQ4; Q96KM6: ZNF512B; NbExp=3; IntAct=EBI-747107, EBI-1049952; CC Q8IUQ4; Q59GP6; NbExp=3; IntAct=EBI-747107, EBI-10243413; CC Q8IUQ4; Q64693: Pou2af1; Xeno; NbExp=5; IntAct=EBI-747107, EBI-943530; CC Q8IUQ4; Q69ZI1: Sh3rf1; Xeno; NbExp=5; IntAct=EBI-747107, EBI-957380; CC Q8IUQ4; P69713: X; Xeno; NbExp=4; IntAct=EBI-747107, EBI-7088789; CC Q8IUQ4-2; Q06481-5: APLP2; NbExp=3; IntAct=EBI-11522811, EBI-25646567; CC Q8IUQ4-2; P05067: APP; NbExp=3; IntAct=EBI-11522811, EBI-77613; CC Q8IUQ4-2; P05067-2: APP; NbExp=3; IntAct=EBI-11522811, EBI-17264467; CC Q8IUQ4-2; Q86V38: ATN1; NbExp=3; IntAct=EBI-11522811, EBI-11954292; CC Q8IUQ4-2; P54253: ATXN1; NbExp=3; IntAct=EBI-11522811, EBI-930964; CC Q8IUQ4-2; A0A0S2Z4M1: AXIN1; NbExp=3; IntAct=EBI-11522811, EBI-16429430; CC Q8IUQ4-2; O95817: BAG3; NbExp=3; IntAct=EBI-11522811, EBI-747185; CC Q8IUQ4-2; O95429: BAG4; NbExp=3; IntAct=EBI-11522811, EBI-2949658; CC Q8IUQ4-2; Q96A83-2: COL26A1; NbExp=3; IntAct=EBI-11522811, EBI-21553822; CC Q8IUQ4-2; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-11522811, EBI-9087876; CC Q8IUQ4-2; P05111: INHA; NbExp=3; IntAct=EBI-11522811, EBI-10194422; CC Q8IUQ4-2; Q92876: KLK6; NbExp=3; IntAct=EBI-11522811, EBI-2432309; CC Q8IUQ4-2; Q9NS86: LANCL2; NbExp=3; IntAct=EBI-11522811, EBI-2510837; CC Q8IUQ4-2; Q8TC57: M1AP; NbExp=3; IntAct=EBI-11522811, EBI-748182; CC Q8IUQ4-2; Q9UPY8: MAPRE3; NbExp=3; IntAct=EBI-11522811, EBI-726739; CC Q8IUQ4-2; O75376: NCOR1; NbExp=3; IntAct=EBI-11522811, EBI-347233; CC Q8IUQ4-2; Q9BSJ6: PIMREG; NbExp=3; IntAct=EBI-11522811, EBI-2568609; CC Q8IUQ4-2; Q8WWY3: PRPF31; NbExp=3; IntAct=EBI-11522811, EBI-1567797; CC Q8IUQ4-2; P86480: PRR20D; NbExp=3; IntAct=EBI-11522811, EBI-12754095; CC Q8IUQ4-2; Q9H082: RAB33B; NbExp=3; IntAct=EBI-11522811, EBI-3048549; CC Q8IUQ4-2; Q96B01: RAD51AP1; NbExp=3; IntAct=EBI-11522811, EBI-1178724; CC Q8IUQ4-2; P28702-3: RXRB; NbExp=3; IntAct=EBI-11522811, EBI-16429492; CC Q8IUQ4-2; Q5VUG0: SFMBT2; NbExp=3; IntAct=EBI-11522811, EBI-12025260; CC Q8IUQ4-2; Q13148: TARDBP; NbExp=3; IntAct=EBI-11522811, EBI-372899; CC Q8IUQ4-2; Q9BTV4: TMEM43; NbExp=3; IntAct=EBI-11522811, EBI-721293; CC Q8IUQ4-2; P61086: UBE2K; NbExp=6; IntAct=EBI-11522811, EBI-473850; CC Q8IUQ4-2; A0A0S2Z639: UPP2; NbExp=3; IntAct=EBI-11522811, EBI-16440814; CC Q8IUQ4-2; A0A0S2Z6U5: UPP2; NbExp=3; IntAct=EBI-11522811, EBI-16432858; CC Q8IUQ4-2; O95045-2: UPP2; NbExp=6; IntAct=EBI-11522811, EBI-11528386; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Predominantly CC cytoplasmic. Partially nuclear. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8IUQ4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IUQ4-2; Sequence=VSP_010166; CC Name=3; Synonyms=Siah-1S; CC IsoId=Q8IUQ4-3; Sequence=VSP_029210, VSP_029211; CC -!- TISSUE SPECIFICITY: Widely expressed at a low level. Down-regulated in CC advanced hepatocellular carcinomas. {ECO:0000269|PubMed:12557228, CC ECO:0000269|PubMed:9403064}. CC -!- INDUCTION: May be induced by p53/TP53, suggesting that it may be CC required to modulate p53/TP53 response. The relevance of such activity CC in vivo is however unclear and may not exist. CC -!- DOMAIN: The RING-type zinc finger domain is essential for ubiquitin CC ligase activity. CC -!- DOMAIN: The SBD domain (substrate-binding domain) mediates the CC homodimerization and the interaction with substrate proteins. It is CC related to the TRAF family. {ECO:0000250|UniProtKB:P61092}. CC -!- PTM: Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation CC disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal CC degradation of HIPK2. {ECO:0000269|PubMed:18536714}. CC -!- DISEASE: Buratti-Harel syndrome (BURHAS) [MIM:619314]: An autosomal CC dominant neurodevelopmental disorder characterized by hypotonia CC apparent in early infancy, global developmental delay, delayed walking, CC language and speech delay, impaired intellectual development, and CC dysmorphic facial features. {ECO:0000269|PubMed:32430360}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the SINA (Seven in absentia) family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U63295; AAC12950.1; -; mRNA. DR EMBL; U76247; AAC51907.1; -; mRNA. DR EMBL; AJ400626; CAC35542.1; -; Genomic_DNA. DR EMBL; EF026094; ABK15529.1; -; mRNA. DR EMBL; BX647064; CAE46191.1; -; mRNA. DR EMBL; BC035562; AAH35562.1; -; mRNA. DR EMBL; BC042550; AAH42550.1; -; mRNA. DR EMBL; BC044920; AAH44920.1; -; mRNA. DR CCDS; CCDS10735.1; -. [Q8IUQ4-1] DR CCDS; CCDS32444.1; -. [Q8IUQ4-2] DR RefSeq; NP_001006611.1; NM_001006610.2. [Q8IUQ4-2] DR RefSeq; NP_003022.3; NM_003031.3. [Q8IUQ4-1] DR RefSeq; XP_006721309.1; XM_006721246.3. [Q8IUQ4-1] DR RefSeq; XP_024306163.1; XM_024450395.2. [Q8IUQ4-1] DR RefSeq; XP_054169685.1; XM_054313710.1. [Q8IUQ4-1] DR RefSeq; XP_054169686.1; XM_054313711.1. [Q8IUQ4-1] DR PDB; 2A25; X-ray; 2.20 A; A=90-282. DR PDB; 4C9Z; X-ray; 1.95 A; A/B=91-282. DR PDB; 4CA1; X-ray; 1.58 A; A/B=91-282. DR PDB; 4I7B; X-ray; 3.00 A; A/C=90-282. DR PDB; 4I7C; X-ray; 2.80 A; A/C=90-282. DR PDB; 4I7D; X-ray; 2.40 A; A/C=90-282. DR PDB; 4X3G; X-ray; 2.34 A; A/B=91-282. DR PDB; 5WZZ; X-ray; 2.10 A; A/B/C/D=93-282. DR PDB; 8HEO; X-ray; 2.53 A; A/B=89-282. DR PDB; 9G0L; X-ray; 1.90 A; A=28-125. DR PDBsum; 2A25; -. DR PDBsum; 4C9Z; -. DR PDBsum; 4CA1; -. DR PDBsum; 4I7B; -. DR PDBsum; 4I7C; -. DR PDBsum; 4I7D; -. DR PDBsum; 4X3G; -. DR PDBsum; 5WZZ; -. DR PDBsum; 8HEO; -. DR PDBsum; 9G0L; -. DR AlphaFoldDB; Q8IUQ4; -. DR SMR; Q8IUQ4; -. DR BioGRID; 112372; 234. DR CORUM; Q8IUQ4; -. DR DIP; DIP-35684N; -. DR FunCoup; Q8IUQ4; 3423. DR IntAct; Q8IUQ4; 158. DR MINT; Q8IUQ4; -. DR NDEx; IQUERY-CP-SIAH1; 7 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000349156; -. DR MoonDB; Q8IUQ4; Predicted. DR TCDB; 8.A.133.1.1; the siah1 e3 ubiquitin-protein ligase (siah1) family. DR GlyGen; Q8IUQ4; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q8IUQ4; -. DR PhosphoSitePlus; Q8IUQ4; -. DR BioMuta; SIAH1; -. DR DMDM; 46577493; -. DR jPOST; Q8IUQ4; -. DR MassIVE; Q8IUQ4; -. DR PaxDb; 9606-ENSP00000349156; -. DR PeptideAtlas; Q8IUQ4; -. DR ProteomicsDB; 70593; -. [Q8IUQ4-1] DR ProteomicsDB; 70594; -. [Q8IUQ4-2] DR ProteomicsDB; 70595; -. [Q8IUQ4-3] DR Pumba; Q8IUQ4; -. DR Antibodypedia; 14482; 409 antibodies from 35 providers. DR DNASU; 6477; -. DR Ensembl; ENST00000356721.3; ENSP00000349156.3; ENSG00000196470.13. [Q8IUQ4-2] DR Ensembl; ENST00000380006.2; ENSP00000369343.2; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000394725.3; ENSP00000378214.2; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000568007.5; ENSP00000456421.1; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000893204.1; ENSP00000563263.1; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000893205.1; ENSP00000563264.1; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000893206.1; ENSP00000563265.1; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000893207.1; ENSP00000563266.1; ENSG00000196470.13. [Q8IUQ4-1] DR Ensembl; ENST00000939086.1; ENSP00000609145.1; ENSG00000196470.13. [Q8IUQ4-1] DR GeneID; 6477; -. DR KEGG; hsa:6477; -. DR MANE-Select; ENST00000394725.3; ENSP00000378214.2; NM_003031.4; NP_003022.3. DR UCSC; uc002efl.4; human. [Q8IUQ4-1] DR AGR; HGNC:10857; -. DR ClinPGx; PA35759; -. DR CTD; 6477; -. DR DisGeNET; 6477; -. DR GeneCards; SIAH1; -. DR HGNC; HGNC:10857; SIAH1. DR HPA; ENSG00000196470; Low tissue specificity. DR MalaCards; SIAH1; -. DR MIM; 602212; gene. DR MIM; 619314; phenotype. DR OpenTargets; ENSG00000196470; -. DR Orphanet; 528084; Non-specific syndromic intellectual disability. DR VEuPathDB; HostDB:ENSG00000196470; -. DR eggNOG; KOG3002; Eukaryota. DR GeneTree; ENSGT00940000154837; -. DR HOGENOM; CLU_028215_0_0_1; -. DR InParanoid; Q8IUQ4; -. DR OMA; HSNTGCT; -. DR OrthoDB; 941555at2759; -. DR PAN-GO; Q8IUQ4; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q8IUQ4; -. DR PathwayCommons; Q8IUQ4; -. DR Reactome; R-HSA-373752; Netrin-1 signaling. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q8IUQ4; -. DR SIGNOR; Q8IUQ4; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000196470; -. DR BioGRID-ORCS; 6477; 38 hits in 1224 CRISPR screens. DR ChiTaRS; SIAH1; human. DR EvolutionaryTrace; Q8IUQ4; -. DR GeneWiki; SIAH1; -. DR GenomeRNAi; 6477; -. DR Pharos; Q8IUQ4; Tbio. DR PRO; PR:Q8IUQ4; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q8IUQ4; protein. DR Bgee; ENSG00000196470; Expressed in secondary oocyte and 204 other cell types or tissues. DR ExpressionAtlas; Q8IUQ4; baseline and differential. DR GO; GO:0030877; C:beta-catenin destruction complex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IBA:GO_Central. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IMP:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome. DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0007411; P:axon guidance; TAS:ProtInc. DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:0007399; P:nervous system development; TAS:ProtInc. DR GO; GO:0051402; P:neuron apoptotic process; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0031648; P:protein destabilization; IEA:Ensembl. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR GO; GO:0007283; P:spermatogenesis; IEA:UniProtKB-KW. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI. DR CDD; cd03829; Sina; 1. DR DisProt; DP02608; -. DR FunFam; 2.60.210.10:FF:000002; E3 ubiquitin-protein ligase; 1. DR FunFam; 3.30.160.60:FF:000665; E3 ubiquitin-protein ligase; 1. DR FunFam; 3.30.40.10:FF:000050; E3 ubiquitin-protein ligase; 1. DR FunFam; 3.30.40.10:FF:000063; E3 ubiquitin-protein ligase; 1. DR Gene3D; 2.60.210.10; Apoptosis, Tumor Necrosis Factor Receptor Associated Protein 2, Chain A; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 2. DR IDEAL; IID00120; -. DR InterPro; IPR018121; 7-in-absentia-prot_TRAF-dom. DR InterPro; IPR004162; SINA-like_animal. DR InterPro; IPR049548; Sina-like_RING. DR InterPro; IPR008974; TRAF-like. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR013010; Znf_SIAH. DR PANTHER; PTHR45877:SF7; E3 UBIQUITIN-PROTEIN LIGASE SIAH1; 1. DR PANTHER; PTHR45877; E3 UBIQUITIN-PROTEIN LIGASE SIAH2; 1. DR Pfam; PF21362; Sina_RING; 1. DR Pfam; PF03145; Sina_TRAF; 1. DR Pfam; PF21361; Sina_ZnF; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF49599; TRAF domain-like; 1. DR PROSITE; PS50089; ZF_RING_2; 1. DR PROSITE; PS51081; ZF_SIAH; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Cell cycle; Cytoplasm; KW Developmental protein; Differentiation; Disease variant; KW Intellectual disability; Metal-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Spermatogenesis; KW Transferase; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..282 FT /note="E3 ubiquitin-protein ligase SIAH1" FT /id="PRO_0000056163" FT ZN_FING 41..76 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT ZN_FING 93..153 FT /note="SIAH-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00455" FT REGION 1..22 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 90..282 FT /note="SBD" FT /evidence="ECO:0000250|UniProtKB:P61092" FT COMPBIAS 1..17 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 98 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:28546513, FT ECO:0007744|PDB:5WZZ" FT BINDING 105 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:28546513, FT ECO:0007744|PDB:5WZZ" FT BINDING 117 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:28546513, FT ECO:0007744|PDB:5WZZ" FT BINDING 121 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:28546513, FT ECO:0007744|PDB:5WZZ" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16085652, FT ECO:0000269|PubMed:28546513, ECO:0007744|PDB:2A25, FT ECO:0007744|PDB:5WZZ" FT BINDING 135 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16085652, FT ECO:0000269|PubMed:28546513, ECO:0007744|PDB:2A25, FT ECO:0007744|PDB:5WZZ" FT BINDING 147 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16085652, FT ECO:0000269|PubMed:28546513, ECO:0007744|PDB:2A25, FT ECO:0007744|PDB:5WZZ" FT BINDING 152 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16085652, FT ECO:0000269|PubMed:28546513, ECO:0007744|PDB:2A25, FT ECO:0007744|PDB:5WZZ" FT MOD_RES 19 FT /note="Phosphoserine; by ATM and ATR" FT /evidence="ECO:0000269|PubMed:18536714" FT VAR_SEQ 1 FT /note="M -> MTGKATPPSLYSWRGVLFTCLPAARTRKRKEM (in isoform FT 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:17974005" FT /id="VSP_010166" FT VAR_SEQ 193..195 FT /note="LEK -> DLS (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17420721" FT /id="VSP_029210" FT VAR_SEQ 196..282 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17420721" FT /id="VSP_029211" FT VARIANT 41 FT /note="C -> G (in BURHAS; loss of function in Wnt signaling FT pathway)" FT /evidence="ECO:0000269|PubMed:32430360" FT /id="VAR_085780" FT VARIANT 50 FT /note="P -> L (in BURHAS)" FT /evidence="ECO:0000269|PubMed:32430360" FT /id="VAR_085781" FT VARIANT 128 FT /note="C -> F (in BURHAS; loss of function in Wnt signaling FT pathway)" FT /evidence="ECO:0000269|PubMed:32430360" FT /id="VAR_085782" FT VARIANT 168 FT /note="T -> A (in BURHAS; loss of function in Wnt signaling FT pathway)" FT /evidence="ECO:0000269|PubMed:32430360" FT /id="VAR_085783" FT VARIANT 174 FT /note="G -> R (in BURHAS; loss of function in Wnt signaling FT pathway)" FT /evidence="ECO:0000269|PubMed:32430360" FT /id="VAR_085784" FT MUTAGEN 19 FT /note="S->A: Impaired ATM mediated phosphorylation, but FT normal interaction with HIPK2 and HIPK2 subsequent FT proteasomal degradation." FT /evidence="ECO:0000269|PubMed:18536714" FT MUTAGEN 19 FT /note="S->D: Reduced interaction with HIPK2 and HIPK2 FT subsequent proteasomal degradation." FT /evidence="ECO:0000269|PubMed:18536714" FT MUTAGEN 40 FT /note="E->R: Loss of function." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 41 FT /note="C->S: Loss of function; when associated with S-44." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 44 FT /note="C->S: Loss of function." FT /evidence="ECO:0000269|PubMed:18536714, FT ECO:0000269|PubMed:9858595" FT MUTAGEN 55 FT /note="C->A: Loss of function; when associated with A-59 FT and S-72." FT /evidence="ECO:0000269|PubMed:15064394, FT ECO:0000269|PubMed:9858595" FT MUTAGEN 55 FT /note="C->S: Loss of function; when associated with Y-59." FT /evidence="ECO:0000269|PubMed:15064394, FT ECO:0000269|PubMed:9858595" FT MUTAGEN 59 FT /note="H->A: Loss of function; when associated with A-55 FT and S-72." FT /evidence="ECO:0000269|PubMed:15064394, FT ECO:0000269|PubMed:9858595" FT MUTAGEN 59 FT /note="H->Y: Loss of function." FT /evidence="ECO:0000269|PubMed:15064394, FT ECO:0000269|PubMed:9858595" FT MUTAGEN 66 FT /note="R->L: Decreased activity; when associated with FT T-68." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 68 FT /note="K->T: Decreased activity; when associated with FT L-66." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 72 FT /note="C->S: Loss of function; when associated with A-55 FT and A-59." FT /evidence="ECO:0000269|PubMed:15064394" FT MUTAGEN 76 FT /note="R->E: Decreased activity." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 124 FT /note="R->A: In D; does not impair its ability to interact FT with CACYBP and degrade CTNNB1 and PML; when associated FT with A-214; A-215; A-231 and A-232." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 142 FT /note="D->A: In E; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-151." FT /evidence="ECO:0000269|PubMed:12421809" FT MUTAGEN 151 FT /note="Q->A: In E; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-142." FT /evidence="ECO:0000269|PubMed:12421809" FT MUTAGEN 152 FT /note="H->Y: Abolishes ability to degrade DCC." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 161..162 FT /note="ED->AA: In A; does not impair its ability to degrade FT PML while it abolishes its ability to interact with CACYBP FT and degrade CTNNB1; when associated with A-226 and A-237." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 198..200 FT /note="KYD->GDG: Impairs CTNNB1 degradation." FT /evidence="ECO:0000269|PubMed:16085652" FT MUTAGEN 202 FT /note="H->Y: No effect." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 211 FT /note="L->R: Abolishes ability to degrade DCC." FT /evidence="ECO:0000269|PubMed:9858595" FT MUTAGEN 214..215 FT /note="TR->AA: In D; does not impair its ability to FT interact with CACYBP and degrade CTNNB1 and PML; when FT associated with A-124; A-231 and A-232." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 224 FT /note="R->A: In C; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-233." FT /evidence="ECO:0000269|PubMed:12421809" FT MUTAGEN 226 FT /note="E->A: In A; does not impair its ability to degrade FT PML while it abolishes its ability to interact with CACYBP FT and degrade CTNNB1; when associated with A-161; A-162 and FT A-237." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 231..232 FT /note="RR->AA: In D; does not impair its ability to FT interact with CACYBP and degrade CTNNB1 and PML; when FT associated with A-124; A-214 and A-215." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 233 FT /note="R->A: In C; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-233." FT /evidence="ECO:0000269|PubMed:12421809" FT MUTAGEN 237 FT /note="E->A: In A; does not impair its ability to degrade FT PML while it abolishes its ability to interact with CACYBP FT and degrade CTNNB1; when associated with A-161; A-162 and FT A-226." FT /evidence="ECO:0000269|PubMed:12421809, FT ECO:0000269|PubMed:14645235" FT MUTAGEN 252 FT /note="M->D,K: Impairs CTNNB1 degradation." FT /evidence="ECO:0000269|PubMed:16085652" FT MUTAGEN 253 FT /note="N->A: In B; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-265." FT /evidence="ECO:0000269|PubMed:12421809" FT MUTAGEN 265 FT /note="Q->A: In B; does not impair its ability to interact FT with CACYBP and degrade CTNNB1; when associated with FT A-253." FT /evidence="ECO:0000269|PubMed:12421809" FT CONFLICT 173 FT /note="P -> S (in Ref. 5; CAE46191)" FT /evidence="ECO:0000305" FT CONFLICT 245 FT /note="E -> G (in Ref. 5; CAE46191)" FT /evidence="ECO:0000305" FT HELIX 32..37 FT /evidence="ECO:0007829|PDB:9G0L" FT TURN 42..44 FT /evidence="ECO:0007829|PDB:9G0L" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:9G0L" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:9G0L" FT TURN 73..75 FT /evidence="ECO:0007829|PDB:9G0L" FT HELIX 85..91 FT /evidence="ECO:0007829|PDB:9G0L" FT HELIX 92..95 FT /evidence="ECO:0007829|PDB:4CA1" FT HELIX 101..103 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 108..110 FT /evidence="ECO:0007829|PDB:4X3G" FT HELIX 111..120 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 122..124 FT /evidence="ECO:0007829|PDB:4I7B" FT STRAND 130..134 FT /evidence="ECO:0007829|PDB:4CA1" FT HELIX 141..151 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 156..167 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 172..184 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 187..197 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 199..201 FT /evidence="ECO:0007829|PDB:5WZZ" FT STRAND 203..213 FT /evidence="ECO:0007829|PDB:4CA1" FT HELIX 215..218 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 221..229 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 232..238 FT /evidence="ECO:0007829|PDB:4CA1" FT TURN 243..245 FT /evidence="ECO:0007829|PDB:4CA1" FT HELIX 248..252 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 256..260 FT /evidence="ECO:0007829|PDB:4CA1" FT HELIX 261..267 FT /evidence="ECO:0007829|PDB:4CA1" FT STRAND 272..281 FT /evidence="ECO:0007829|PDB:4CA1" SQ SEQUENCE 282 AA; 31123 MW; FA0698D0DC1B0A15 CRC64; MSRQTATALP TGTSKCPPSQ RVPALTGTTA SNNDLASLFE CPVCFDYVLP PILQCQSGHL VCSNCRPKLT CCPTCRGPLG SIRNLAMEKV ANSVLFPCKY ASSGCEITLP HTEKADHEEL CEFRPYSCPC PGASCKWQGS LDAVMPHLMH QHKSITTLQG EDIVFLATDI NLPGAVDWVM MQSCFGFHFM LVLEKQEKYD GHQQFFAIVQ LIGTRKQAEN FAYRLELNGH RRRLTWEATP RSIHEGIATA IMNSDCLVFD TSIAQLFAEN GNLGINVTIS MC //