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Identification
HMDB Protein ID HMDBP09307
Secondary Accession Numbers
  • 15139
Name E3 ubiquitin-protein ligase SIAH1
Synonyms
  1. Seven in absentia homolog 1
  2. Siah-1
  3. Siah-1a
Gene Name SIAH1
Protein Type Enzyme
Biological Properties
General Function Involved in ubiquitin-dependent protein catabolic process
Specific Function 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 (MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), 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. 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
Pathways Not Available
Reactions Not Available
GO Classification
Component
organelle
membrane-bounded organelle
intracellular membrane-bounded organelle
nucleus
Function
ion binding
cation binding
metal ion binding
binding
catalytic activity
small conjugating protein ligase activity
transition metal ion binding
zinc ion binding
ligase activity
protein binding
ligase activity, forming carbon-nitrogen bonds
acid-amino acid ligase activity
ubiquitin-protein ligase activity
Process
metabolic process
multicellular organismal process
macromolecule metabolic process
multicellular organismal development
protein modification by small protein conjugation or removal
protein modification by small protein conjugation
protein ubiquitination
catabolic process
macromolecule catabolic process
cellular macromolecule catabolic process
modification-dependent macromolecule catabolic process
modification-dependent protein catabolic process
ubiquitin-dependent protein catabolic process
macromolecule modification
protein modification process
Cellular Location
  1. Nucleus
  2. Cytoplasm
Gene Properties
Chromosome Location Chromosome:1
Locus 16q12
SNPs SIAH1
Gene Sequence
>849 bp
ATGAGCCGTCAGACTGCTACAGCATTACCTACCGGTACCTCGAAGTGTCCACCATCCCAG
AGGGTGCCTGCCCTGACTGGCACAACTGCATCCAACAATGACTTGGCGAGTCTTTTTGAG
TGTCCAGTCTGCTTTGACTATGTGTTACCGCCCATTCTTCAATGTCAGAGTGGCCATCTT
GTTTGTAGCAACTGTCGCCCAAAGCTCACATGTTGTCCAACTTGCCGGGGCCCTTTGGGA
TCCATTCGCAACTTGGCTATGGAGAAAGTGGCTAATTCAGTACTTTTCCCCTGTAAATAT
GCGTCTTCTGGATGTGAAATAACTCTGCCACACACAGAAAAAGCAGACCATGAAGAGCTC
TGTGAGTTTAGGCCTTATTCCTGTCCGTGCCCTGGTGCTTCCTGTAAATGGCAAGGCTCT
CTGGATGCTGTAATGCCCCATCTGATGCATCAGCATAAGTCCATTACAACCCTACAGGGA
GAGGATATAGTTTTTCTTGCTACAGACATTAATCTTCCTGGTGCTGTTGACTGGGTGATG
ATGCAGTCCTGTTTTGGCTTTCACTTCATGTTAGTCTTAGAGAAACAGGAAAAATACGAT
GGTCACCAGCAGTTCTTCGCAATCGTACAGCTGATAGGAACACGCAAGCAAGCTGAAAAT
TTTGCTTACCGACTTGAGCTAAATGGTCATAGGCGACGATTGACTTGGGAAGCGACTCCT
CGATCTATTCATGAAGGAATTGCAACAGCCATTATGAATAGCGACTGTCTAGTCTTTGAC
ACCAGCATTGCACAGCTTTTTGCAGAAAATGGCAATTTAGGCATCAATGTAACTATTTCC
ATGTGTTGA
Protein Properties
Number of Residues 282
Molecular Weight 31122.6
Theoretical pI 6.8
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • None
Protein Sequence
>E3 ubiquitin-protein ligase SIAH1
MSRQTATALPTGTSKCPPSQRVPALTGTTASNNDLASLFECPVCFDYVLPPILQCQSGHL
VCSNCRPKLTCCPTCRGPLGSIRNLAMEKVANSVLFPCKYASSGCEITLPHTEKADHEEL
CEFRPYSCPCPGASCKWQGSLDAVMPHLMHQHKSITTLQGEDIVFLATDINLPGAVDWVM
MQSCFGFHFMLVLEKQEKYDGHQQFFAIVQLIGTRKQAENFAYRLELNGHRRRLTWEATP
RSIHEGIATAIMNSDCLVFDTSIAQLFAENGNLGINVTISMC
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q8IUQ4
UniProtKB/Swiss-Prot Entry Name SIAH1_HUMAN
PDB IDs
GenBank Gene ID U63295
GeneCard ID SIAH1
GenAtlas ID SIAH1
HGNC ID HGNC:10857
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. [PubMed:17974005 ]
  3. 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. [PubMed:11389839 ]
  4. 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. [PubMed:9334332 ]
  5. 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. [PubMed:11389840 ]
  6. 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. [PubMed:10747903 ]
  7. 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. [PubMed:16085652 ]
  8. Nemani M, Linares-Cruz G, Bruzzoni-Giovanelli H, Roperch JP, Tuynder M, Bougueleret L, Cherif D, Medhioub M, Pasturaud P, Alvaro V, der Sarkissan H, Cazes L, Le Paslier D, Le Gall I, Israeli D, Dausset J, Sigaux F, Chumakov I, Oren M, Calvo F, Amson RB, Cohen D, Telerman A: Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9039-42. [PubMed:8799150 ]
  9. Hu G, Chung YL, Glover T, Valentine V, Look AT, Fearon ER: Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Genomics. 1997 Nov 15;46(1):103-11. [PubMed:9403064 ]
  10. Medhioub M, Vaury C, Hamelin R, Thomas G: Lack of somatic mutation in the coding sequence of SIAH1 in tumors hemizygous for this candidate tumor suppressor gene. Int J Cancer. 2000 Sep 15;87(6):794-7. [PubMed:10956387 ]
  11. Mei Y, Xie C, Xie W, Wu Z, Wu M: Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of beta-catenin. Oncogene. 2007 Sep 20;26(43):6319-31. Epub 2007 Apr 9. [PubMed:17420721 ]
  12. Matsuzawa S, Takayama S, Froesch BA, Zapata JM, Reed JC: p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1. EMBO J. 1998 May 15;17(10):2736-47. [PubMed:9582267 ]
  13. 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. [PubMed:9858595 ]
  14. 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. [PubMed:11146551 ]
  15. 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. [PubMed:11483517 ]
  16. 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. [PubMed:11483518 ]
  17. 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. [PubMed:11752454 ]
  18. 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. [PubMed:12072443 ]
  19. 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. [PubMed:14506261 ]
  20. Okabe H, Satoh S, Furukawa Y, Kato T, Hasegawa S, Nakajima Y, Yamaoka Y, Nakamura Y: Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer Res. 2003 Jun 15;63(12):3043-8. [PubMed:12810624 ]
  21. Matsuo K, Satoh S, Okabe H, Nomura A, Maeda T, Yamaoka Y, Ikai I: SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Genes Chromosomes Cancer. 2003 Mar;36(3):283-91. [PubMed:12557228 ]
  22. 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. [PubMed:14654780 ]
  23. Matsuzawa S, Li C, Ni CZ, Takayama S, Reed JC, Ely KR: Structural analysis of Siah1 and its interactions with Siah-interacting protein (SIP). J Biol Chem. 2003 Jan 17;278(3):1837-40. Epub 2002 Nov 5. [PubMed:12421809 ]
  24. Venables JP, Dalgliesh C, Paronetto MP, Skitt L, Thornton JK, Saunders PT, Sette C, Jones KT, Elliott DJ: SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome. Hum Mol Genet. 2004 Jul 15;13(14):1525-34. Epub 2004 May 26. [PubMed:15163637 ]
  25. 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. [PubMed:14645235 ]
  26. 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. [PubMed:15064394 ]
  27. 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. [PubMed:19224863 ]