ID SIH1_HUMAN STANDARD; PRT; 282 AA. AC Q8IUQ4; O43269; Q92880; DT 05-JUL-2004 (Rel. 44, Created) DT 05-JUL-2004 (Rel. 44, Last sequence update) DT 25-JAN-2005 (Rel. 46, Last annotation update) DE Ubiquitin ligase SIAH1 (EC 6.3.2.-) (Seven in absentia homolog 1) DE (Siah-1) (Siah-1a). GN Name=SIAH1; Synonyms=HUMSIAH; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE (ISOFORM 1). RC TISSUE=Intestinal epithelium; RX MEDLINE=96392362; 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 RT apoptosis and tumor suppression."; RL Proc. Natl. Acad. Sci. U.S.A. 93:9039-9042(1996). RN [2] RP NUCLEOTIDE SEQUENCE (ISOFORM 1), SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Fetal brain; RX MEDLINE=98066768; 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 RT absentia (sina) gene."; RL Genomics 46:103-111(1997). RN [3] RP NUCLEOTIDE SEQUENCE. RX PubMed=10956387; 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 (ISOFORM 2). RC TISSUE=Retina; RG The German cDNA consortium; RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2). RC TISSUE=Brain, and Pancreas; RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899; RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G., RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D., RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K., RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F., RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L., RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E., RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C., RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J., RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H., RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W., RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A., RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A., RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G., RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C., RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M., RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E., RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.; RT "Generation and initial analysis of more than 15,000 full-length human RT and mouse cDNA sequences."; RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002). RN [6] RP FUNCTION IN DEGRADATION OF DCC, SUBCELLULAR LOCATION, AND INTERACTION RP WITH UBE2I. RX PubMed=9334332; 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 RT ubiquitin-proteasome pathway."; RL Genes Dev. 11:2701-2714(1997). RN [7] 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 [8] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-40; CYS-41; RP CYS-44; CYS-55; HIS-59; ARG-66; LYS-68; ARG-76; HIS-152; HIS-202 AND RP LEU-211. RX PubMed=9858595; RA Hu G., Fearon E.R.; RT "Siah-1 N-terminal RING domain is required for proteolysis function, RT and C-terminal sequences regulate oligomerization and binding to RT target proteins."; RL Mol. Cell. Biol. 19:724-732(1999). RN [9] 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 RT the proteasome pathway during mitosis."; RL Oncogene 19:5997-6006(2000). RN [10] 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., RA Matsuzawa S.-I., Reed J.C., Ishii S.; RT "p53 suppresses the c-Myb-induced activation of heat shock RT transcription factor 3."; RL J. Biol. Chem. 275:15578-15585(2000). RN [11] RP FUNCTION IN DEGRADATION OF CTNNB1, AND SUBUNIT OF A COMPLEX WITH RP UBE2D1; CACYBP; SKP1A; APC AND TBL1X. RX PubMed=11389839; DOI=10.1016/S1097-2765(01)00242-8; RA Matsuzawa S.-I., 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 [12] 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., RA White R.L., Matsunami N.; RT "Siah-1 mediates a novel beta-catenin degradation pathway linking p53 RT to the adenomatous polyposis coli protein."; RL Mol. Cell 7:927-936(2001). RN [13] 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 RT transcriptional coactivator OBF-1."; RL EMBO J. 20:4143-4152(2001). RN [14] 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 [15] 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., RA Prieur S., Privat N., Tuynder M., Gendron M.-C., Israeel A., Amson R., RA Oren M., 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 [16] RP FUNCTION IN DEGRADATION OF TIEG1. RX PubMed=12072443; DOI=10.1074/jbc.M204812200; RA Johnsen S.A., Subramaniam M., Monroe D.G., Janknecht R., RA Spelsberg T.C.; RT "Modulation of transforming growth factor beta (TGFbeta)/Smad RT transcriptional responses through targeted degradation of TGFbeta- RT inducible early gene-1 by human seven in absentia homologue."; RL J. Biol. Chem. 277:30754-30759(2002). RN [17] 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., RA Iseki E., 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 [18] 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 [19] RP TISSUE SPECIFICITY. RX PubMed=12557228; DOI=10.1002/gcc.10170; RA Matsuo K., Satoh S., Okabe H., Nomura A., Maeda T., Yamaoka Y., RA Ikai I.; RT "SIAH1 inactivation correlates with tumor progression in RT hepatocellular carcinomas."; RL Genes Chromosomes Cancer 36:283-291(2003). RN [20] 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 RT proteasome pathway."; RL Oncogene 22:8845-8851(2003). RN [21] RP INTERACTION WITH CACYBP, AND MUTANTS A; B; C; D AND E. RX PubMed=12421809; DOI=10.1074/jbc.M210263200; RA Matsuzawa S.-I., Li C., Ni C.-Z., Takayama S., Reed J.C., Ely K.R.; RT "Structural analysis of Siah1 and its interactions with Siah- RT interacting protein (SIP)."; RL J. Biol. Chem. 278:1837-1840(2003). RN [22] 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.-I., 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 RT proteasome."; RL J. Biol. Chem. 279:5374-5379(2004). CC -!- FUNCTION: E3 ubiquitin ligase protein that mediates ubiquitination CC and subsequent proteasomal degradation of target proteins. E3 CC ubiquitin ligases accept ubiquitin from an E2 ubiquitin- CC conjugating enzyme in the form of a thioester and then directly CC transfers the ubiquitin to targeted substrates. Mediates E3 CC ubiquitin ligase activity either through direct binding to CC substrates or by functioning as the essential RING domain subunit CC of larger E3 complexes. Triggers the ubiquitin-mediated CC degradation of many substrates, including proteins involved in CC transcription regulation (MYB, POU2AF1, PML and RBBP8), a cell CC surface receptor (DCC), cytoplasmic signal transduction molecules CC (TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule CC motor protein (KIF22), a protein involved in synaptic vesicle CC function in neurons (SYP), a structural protein (CTNNB1) and CC SNCAIP. It is thereby involved in many cellular processes such as CC apoptosis, tumor suppression, cell cycle, axon guidance, CC transcription regulation, spermatogenesis and TNF-alpha signaling. CC Has some overlapping function with SIAH2. CC -!- PATHWAY: Ubiquitin conjugation; third step. CC -!- SUBUNIT: Homodimer. Interacts with group 1 glutamate receptors CC GRM1 and GRM5. Interacts with DAB1, which may inhibit its CC activity. Interacts with UBE2E2 (By similarity). Component of some CC large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1A, APC CC and TBL1X. Interacts with UBE2I. Interacts with alpha-tubulin. CC Interacts with PEG10, which may inhibit its activity. CC -!- SUBCELLULAR LOCATION: Cytoplasmic; predominantly. Nuclear; CC partially. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8IUQ4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IUQ4-2; Sequence=VSP_010166; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Widely expressed at low level. Down-regulated CC in advanced hepatocellular carcinomas. CC -!- INDUCTION: May be induced by TP53/p53, suggesting that it may be CC required to modulate 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 CC ubiquitin ligase activity. CC -!- DOMAIN: The SBD domain (substrate-binding domain) mediates the CC homodimerization and the interaction with substrate proteins. It CC is related to the TRAF family (By similarity). CC -!- SIMILARITY: Belongs to the SINA (Seven in absentia) family. CC -!- SIMILARITY: Contains 1 C2HC-type zinc finger. CC -!- SIMILARITY: Contains 1 RING-type zinc finger. CC -!- SIMILARITY: Contains 1 SIAH-type zinc finger. 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; -. DR EMBL; U76247; AAC51907.1; -. DR EMBL; AJ400626; CAC35542.1; -. DR EMBL; BX647064; CAE46191.1; -. DR EMBL; BC035562; AAH35562.1; -. DR EMBL; BC042550; AAH42550.1; -. DR HSSP; Q06984; 1K2F. DR Ensembl; ENSG00000196470; Homo sapiens. DR Genew; HGNC:10857; SIAH1. DR H-InvDB; HIX0013010; -. DR H-InvDB; HIX0013012; -. DR MIM; 602212; -. DR GO; GO:0008270; F:zinc ion binding; IDA. DR InterPro; IPR004162; Sina. DR InterPro; IPR008974; Traf_dom. DR InterPro; IPR001841; Znf_ring. DR Pfam; PF03145; Sina; 1. DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG. DR PROSITE; PS50089; ZF_RING_2; 1. KW Alternative splicing; Apoptosis; Cell cycle; Ligase; Metal-binding; KW Nuclear protein; Spermatogenesis; Ubl conjugation pathway; Zinc; KW Zinc-finger. FT ZN_FING 41 76 RING-type. FT ZN_FING 96 121 C2HC-type. FT ZN_FING 126 152 SIAH-type. FT DOMAIN 90 282 SBD. FT METAL 98 98 Zinc 1 (By similarity). FT METAL 105 105 Zinc 1 (By similarity). FT METAL 117 117 Zinc 1 (By similarity). FT METAL 121 121 Zinc 1 (By similarity). FT METAL 128 128 Zinc 2 (By similarity). FT METAL 135 135 Zinc 2 (By similarity). FT METAL 147 147 Zinc 2 (By similarity). FT METAL 152 152 Zinc 2 (By similarity). FT VARSPLIC 1 1 M -> MTGKATPPSLYSWRGVLFTCLPAARTRKRKEM (in FT isoform 2). FT /FTId=VSP_010166. FT MUTAGEN 40 40 E->R: Loss of function. FT MUTAGEN 41 41 C->S: Loss of function; when associated FT with S-44. FT MUTAGEN 44 44 C->S: Loss of function. FT MUTAGEN 55 55 C->S: Loss of function; when associated FT with Y-59. FT MUTAGEN 59 59 H->Y: Loss of function. FT MUTAGEN 66 66 R->L: Decreased activity; when associated FT with T-68. FT MUTAGEN 68 68 K->T: Decreased activity; when associated FT with L-66. FT MUTAGEN 76 76 R->E: Decreased activity. FT MUTAGEN 124 124 R->A: In mutant D; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1 and PML; when associated FT with A-214; A-215; A-231 and A-232. FT MUTAGEN 142 142 D->A: In mutant E; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 151. FT MUTAGEN 151 151 Q->A: In mutant E; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 142. FT MUTAGEN 152 152 H->Y: Abolishes ability to degrade DCC. FT MUTAGEN 161 162 ED->AA: In mutant A; does not impair its FT ability to degrade PML while it abolishes FT its ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 226 and A-237. FT MUTAGEN 202 202 H->Y: No effect. FT MUTAGEN 211 211 L->R: Abolishes ability to degrade DCC. FT MUTAGEN 214 215 TR->AA: In mutant D; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1 and PML; when associated FT with A-124; A-231 and A-232. FT MUTAGEN 224 224 R->A: In mutant C; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 233. FT MUTAGEN 226 226 E->A: In mutant A; does not impair its FT ability to degrade PML while it abolishes FT its ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 161; A-162 and A-237. FT MUTAGEN 231 232 RR->AA: In mutant D; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1 and PML; when associated FT with A-124; A-214 and A-215. FT MUTAGEN 233 233 R->A: In mutant C; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 233. FT MUTAGEN 237 237 E->A: In mutant A; does not impair its FT ability to degrade PML while it abolishes FT its ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 161; A-162 and A-226. FT MUTAGEN 253 253 N->A: In mutant B; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 265. FT MUTAGEN 265 265 Q->A: In mutant B; does not impair its FT ability to interact with CACYBP and FT degrade CTNNB1; when associated with A- FT 253. FT CONFLICT 173 173 P -> S (in Ref. 4). FT CONFLICT 245 245 E -> G (in Ref. 4). 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 //