ID:SIAH1_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase SIAH1; EC=6.3.2.-; AltName: Full=Seven in absentia homolog 1; Short=Siah-1; AltName: Full=Siah-1a; 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), 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. ENZYME REGULATION: Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Homodimer. Interacts with group 1 glutamate receptors GRM1 and GRM5. Interacts with DAB1, which may inhibit its activity. Interacts with UBE2E2. Interacts with PEG3. Interacts with GAPDH; leading to stabilize SIAH1 (By similarity). Component of some large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with UBE2I. Interacts with alpha- tubulin. Interacts with PEG10, which may inhibit its activity. Interacts with KHDRBS3. Interacts with SNCAIP and HIPK2. INTERACTION: O15265:ATXN7; NbExp=2; IntAct=EBI-747107, EBI-708350; Q99836:MYD88; NbExp=3; IntAct=EBI-747107, EBI-447677; O43236-6:SEPT4; NbExp=2; IntAct=EBI-747107, EBI-4372019; Q69ZI1:Sh3rf1 (xeno); NbExp=5; IntAct=EBI-747107, EBI-957380; P98170:XIAP; NbExp=3; IntAct=EBI-747107, EBI-517127; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Predominantly cytoplasmic. Partially nuclear. TISSUE SPECIFICITY: Widely expressed at a low level. Down- regulated in advanced hepatocellular carcinomas. INDUCTION: May be induced by p53/TP53, suggesting that it may be required to modulate p53/TP53 response. The relevance of such activity in vivo is however unclear and may not exist. DOMAIN: The RING-type zinc finger domain is essential for ubiquitin ligase activity. DOMAIN: The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family (By similarity). PTM: Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2. SIMILARITY: Belongs to the SINA (Seven in absentia) family. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 1 SIAH-type zinc finger.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q8IUQ4
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000209 protein polyubiquitination GO:0006511 ubiquitin-dependent protein catabolic process GO:0006915 apoptotic process GO:0007049 cell cycle GO:0007275 multicellular organism development GO:0007283 spermatogenesis GO:0007399 nervous system development GO:0007411 axon guidance GO:0009653 anatomical structure morphogenesis GO:0016567 protein ubiquitination GO:0030154 cell differentiation GO:0030163 protein catabolic process GO:0031648 protein destabilization GO:0043065 positive regulation of apoptotic process GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0044267 cellular protein metabolic process GO:0051402 neuron apoptotic process GO:2001244 positive regulation of intrinsic apoptotic signaling pathway
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
