UniProtKB - Q8IUQ4 (SIAH1_HUMAN)
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Protein
E3 ubiquitin-protein ligase SIAH1
Gene
SIAH1
Organism
Homo sapiens (Human)
Status
Functioni
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.19 Publications
Catalytic activityi
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.
Enzyme regulationi
Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10.1 Publication
Pathwayi: protein ubiquitination
This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.
Sites
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Metal bindingi | 98 | Zinc 1By similarity | 1 | |
| Metal bindingi | 105 | Zinc 1By similarity | 1 | |
| Metal bindingi | 117 | Zinc 1By similarity | 1 | |
| Metal bindingi | 121 | Zinc 1By similarity | 1 | |
| Metal bindingi | 128 | Zinc 2 | 1 | |
| Metal bindingi | 135 | Zinc 2 | 1 | |
| Metal bindingi | 147 | Zinc 2 | 1 | |
| Metal bindingi | 152 | Zinc 2 | 1 |
Regions
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Zinc fingeri | 41 – 76 | RING-typePROSITE-ProRule annotationAdd BLAST | 36 | |
| Zinc fingeri | 93 – 153 | SIAH-typePROSITE-ProRule annotationAdd BLAST | 61 |
GO - Molecular functioni
- identical protein binding Source: IntAct
- protein C-terminus binding Source: UniProtKB
- ubiquitin protein ligase activity Source: MGI
- ubiquitin-protein transferase activity Source: UniProtKB
- zinc ion binding Source: UniProtKB
GO - Biological processi
- anatomical structure morphogenesis Source: ProtInc
- apoptotic process Source: ProtInc
- axon guidance Source: Reactome
- cell cycle Source: UniProtKB-KW
- cellular protein metabolic process Source: Reactome
- nervous system development Source: ProtInc
- neuron apoptotic process Source: UniProtKB
- positive regulation of apoptotic process Source: UniProtKB
- positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
- proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
- protein catabolic process Source: UniProtKB
- protein destabilization Source: Ensembl
- protein polyubiquitination Source: Reactome
- spermatogenesis Source: UniProtKB-KW
- ubiquitin-dependent protein catabolic process Source: MGI
Keywordsi
| Molecular function | Developmental protein, Transferase |
| Biological process | Apoptosis, Cell cycle, Differentiation, Spermatogenesis, Ubl conjugation pathway |
| Ligand | Metal-binding, Zinc |
Enzyme and pathway databases
| BRENDAi | 6.3.2.19 2681 |
| Reactomei | R-HSA-373752 Netrin-1 signaling R-HSA-977225 Amyloid fiber formation R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation |
| SIGNORi | Q8IUQ4 |
| UniPathwayi | UPA00143 |
Protein family/group databases
| MoonDBi | Q8IUQ4 Predicted |
Names & Taxonomyi
| Protein namesi | Recommended name: E3 ubiquitin-protein ligase SIAH1 (EC:2.3.2.27)Alternative name(s): RING-type E3 ubiquitin transferase SIAH1Curated Seven in absentia homolog 1 Short name: Siah-1 Siah-1a |
| Gene namesi | Name:SIAH1 Synonyms:HUMSIAH |
| Organismi | Homo sapiens (Human) |
| Taxonomic identifieri | 9606 [NCBI] |
| Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
| Proteomesi |
|
Organism-specific databases
| EuPathDBi | HostDB:ENSG00000196470.11 |
| HGNCi | HGNC:10857 SIAH1 |
| MIMi | 602212 gene |
| neXtProti | NX_Q8IUQ4 |
Pathology & Biotechi
Mutagenesis
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Mutagenesisi | 19 | S → A: Impaired ATM mediated phosphorylation, but normal interaction with HIPK2 and HIPK2 subsequent proteasomal degradation. 1 Publication | 1 | |
| Mutagenesisi | 19 | S → D: Reduced interaction with HIPK2 and HIPK2 subsequent proteasomal degradation. 1 Publication | 1 | |
| Mutagenesisi | 40 | E → R: Loss of function. 1 Publication | 1 | |
| Mutagenesisi | 41 | C → S: Loss of function; when associated with S-44. 1 Publication | 1 | |
| Mutagenesisi | 44 | C → S: Loss of function. 2 Publications | 1 | |
| Mutagenesisi | 55 | C → A: Loss of function; when associated with A-59 and S-72. 2 Publications | 1 | |
| Mutagenesisi | 55 | C → S: Loss of function; when associated with Y-59. 2 Publications | 1 | |
| Mutagenesisi | 59 | H → A: Loss of function; when associated with A-55 and S-72. 2 Publications | 1 | |
| Mutagenesisi | 59 | H → Y: Loss of function. 2 Publications | 1 | |
| Mutagenesisi | 66 | R → L: Decreased activity; when associated with T-68. 1 Publication | 1 | |
| Mutagenesisi | 68 | K → T: Decreased activity; when associated with L-66. 1 Publication | 1 | |
| Mutagenesisi | 72 | C → S: Loss of function; when associated with A-55 and A-59. 1 Publication | 1 | |
| Mutagenesisi | 76 | R → E: Decreased activity. 1 Publication | 1 | |
| Mutagenesisi | 124 | R → A in D; does not impair its ability to interact with CACYBP and degrade CTNNB1 and PML; when associated with A-214; A-215; A-231 and A-232. | 1 | |
| Mutagenesisi | 142 | D → A in E; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-151. | 1 | |
| Mutagenesisi | 151 | Q → A in E; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-142. | 1 | |
| Mutagenesisi | 152 | H → Y: Abolishes ability to degrade DCC. 1 Publication | 1 | |
| Mutagenesisi | 161 – 162 | ED → AA in A; does not impair its ability to degrade PML while it abolishes its ability to interact with CACYBP and degrade CTNNB1; when associated with A-226 and A-237. | 2 | |
| Mutagenesisi | 198 – 200 | KYD → GDG: Impairs CTNNB1 degradation. 1 Publication | 3 | |
| Mutagenesisi | 202 | H → Y: No effect. 1 Publication | 1 | |
| Mutagenesisi | 211 | L → R: Abolishes ability to degrade DCC. 1 Publication | 1 | |
| Mutagenesisi | 214 – 215 | TR → AA in D; does not impair its ability to interact with CACYBP and degrade CTNNB1 and PML; when associated with A-124; A-231 and A-232. | 2 | |
| Mutagenesisi | 224 | R → A in C; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-233. | 1 | |
| Mutagenesisi | 226 | E → A in A; does not impair its ability to degrade PML while it abolishes its ability to interact with CACYBP and degrade CTNNB1; when associated with A-161; A-162 and A-237. | 1 | |
| Mutagenesisi | 231 – 232 | RR → AA in D; does not impair its ability to interact with CACYBP and degrade CTNNB1 and PML; when associated with A-124; A-214 and A-215. | 2 | |
| Mutagenesisi | 233 | R → A in C; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-233. | 1 | |
| Mutagenesisi | 237 | E → A in A; does not impair its ability to degrade PML while it abolishes its ability to interact with CACYBP and degrade CTNNB1; when associated with A-161; A-162 and A-226. | 1 | |
| Mutagenesisi | 252 | M → D or K: Impairs CTNNB1 degradation. 1 Publication | 1 | |
| Mutagenesisi | 253 | N → A in B; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-265. | 1 | |
| Mutagenesisi | 265 | Q → A in B; does not impair its ability to interact with CACYBP and degrade CTNNB1; when associated with A-253. | 1 |
Organism-specific databases
| DisGeNETi | 6477 |
| OpenTargetsi | ENSG00000196470 |
| PharmGKBi | PA35759 |
Polymorphism and mutation databases
| BioMutai | SIAH1 |
| DMDMi | 46577493 |
PTM / Processingi
Molecule processing
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| ChainiPRO_0000056163 | 1 – 282 | E3 ubiquitin-protein ligase SIAH1Add BLAST | 282 |
Amino acid modifications
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Modified residuei | 19 | Phosphoserine; by ATM and ATR1 Publication | 1 |
Post-translational modificationi
Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2.1 Publication
Keywords - PTMi
PhosphoproteinProteomic databases
| EPDi | Q8IUQ4 |
| MaxQBi | Q8IUQ4 |
| PaxDbi | Q8IUQ4 |
| PeptideAtlasi | Q8IUQ4 |
| PRIDEi | Q8IUQ4 |
| ProteomicsDBi | 70593 70594 [Q8IUQ4-2] 70595 [Q8IUQ4-3] |
PTM databases
| iPTMneti | Q8IUQ4 |
| PhosphoSitePlusi | Q8IUQ4 |
Expressioni
Tissue specificityi
Widely expressed at a low level. Down-regulated in advanced hepatocellular carcinomas.2 Publications
Inductioni
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.
Gene expression databases
| Bgeei | ENSG00000196470 |
| CleanExi | HS_SIAH1 |
| ExpressionAtlasi | Q8IUQ4 baseline and differential |
| Genevisiblei | Q8IUQ4 HS |
Organism-specific databases
| HPAi | CAB018724 |
Interactioni
Subunit structurei
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.By similarity11 Publications
Binary interactionsi
GO - Molecular functioni
- identical protein binding Source: IntAct
- protein C-terminus binding Source: UniProtKB
Protein-protein interaction databases
| BioGridi | 112372, 172 interactors |
| CORUMi | Q8IUQ4 |
| DIPi | DIP-35684N |
| IntActi | Q8IUQ4, 137 interactors |
| MINTi | Q8IUQ4 |
| STRINGi | 9606.ENSP00000349156 |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Beta strandi | 95 – 97 | Combined sources | 3 | |
| Helixi | 101 – 103 | Combined sources | 3 | |
| Beta strandi | 108 – 110 | Combined sources | 3 | |
| Helixi | 111 – 120 | Combined sources | 10 | |
| Beta strandi | 122 – 124 | Combined sources | 3 | |
| Beta strandi | 130 – 134 | Combined sources | 5 | |
| Helixi | 141 – 143 | Combined sources | 3 | |
| Helixi | 144 – 151 | Combined sources | 8 | |
| Beta strandi | 156 – 167 | Combined sources | 12 | |
| Beta strandi | 172 – 184 | Combined sources | 13 | |
| Beta strandi | 187 – 197 | Combined sources | 11 | |
| Beta strandi | 199 – 201 | Combined sources | 3 | |
| Beta strandi | 203 – 213 | Combined sources | 11 | |
| Helixi | 215 – 218 | Combined sources | 4 | |
| Beta strandi | 221 – 229 | Combined sources | 9 | |
| Beta strandi | 232 – 238 | Combined sources | 7 | |
| Turni | 243 – 245 | Combined sources | 3 | |
| Helixi | 248 – 252 | Combined sources | 5 | |
| Beta strandi | 256 – 260 | Combined sources | 5 | |
| Helixi | 261 – 267 | Combined sources | 7 | |
| Beta strandi | 272 – 281 | Combined sources | 10 |
3D structure databases
| ProteinModelPortali | Q8IUQ4 |
| SMRi | Q8IUQ4 |
| ModBasei | Search... |
| MobiDBi | Search... |
Miscellaneous databases
| EvolutionaryTracei | Q8IUQ4 |
Family & Domainsi
Region
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Regioni | 90 – 282 | SBDAdd BLAST | 193 |
Domaini
The RING-type zinc finger domain is essential for ubiquitin ligase activity.
The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.By similarity
Sequence similaritiesi
Belongs to the SINA (Seven in absentia) family.Curated
Zinc finger
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Zinc fingeri | 41 – 76 | RING-typePROSITE-ProRule annotationAdd BLAST | 36 | |
| Zinc fingeri | 93 – 153 | SIAH-typePROSITE-ProRule annotationAdd BLAST | 61 |
Keywords - Domaini
Zinc-fingerPhylogenomic databases
| eggNOGi | KOG3002 Eukaryota ENOG410XVP0 LUCA |
| GeneTreei | ENSGT00390000005434 |
| HOGENOMi | HOG000231487 |
| HOVERGENi | HBG055701 |
| InParanoidi | Q8IUQ4 |
| KOi | K04506 |
| OMAi | EACEFRP |
| OrthoDBi | EOG091G0BPY |
| PhylomeDBi | Q8IUQ4 |
| TreeFami | TF312976 |
Family and domain databases
| Gene3Di | 2.60.210.10, 1 hit 3.30.40.10, 1 hit |
| InterProi | View protein in InterPro IPR018121 7-in-absentia-prot_TRAF-dom IPR004162 SINA-like IPR008974 TRAF-like IPR001841 Znf_RING IPR013083 Znf_RING/FYVE/PHD IPR013010 Znf_SIAH |
| PANTHERi | PTHR10315 PTHR10315, 1 hit |
| Pfami | View protein in Pfam PF03145 Sina, 1 hit |
| SUPFAMi | SSF49599 SSF49599, 1 hit |
| PROSITEi | View protein in PROSITE PS50089 ZF_RING_2, 1 hit PS51081 ZF_SIAH, 1 hit |
Sequences (3)i
Sequence statusi: Complete.
This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform 1 (identifier: Q8IUQ4-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
10 20 30 40 50
MSRQTATALP TGTSKCPPSQ RVPALTGTTA SNNDLASLFE CPVCFDYVLP
60 70 80 90 100
PILQCQSGHL VCSNCRPKLT CCPTCRGPLG SIRNLAMEKV ANSVLFPCKY
110 120 130 140 150
ASSGCEITLP HTEKADHEEL CEFRPYSCPC PGASCKWQGS LDAVMPHLMH
160 170 180 190 200
QHKSITTLQG EDIVFLATDI NLPGAVDWVM MQSCFGFHFM LVLEKQEKYD
210 220 230 240 250
GHQQFFAIVQ LIGTRKQAEN FAYRLELNGH RRRLTWEATP RSIHEGIATA
260 270 280
IMNSDCLVFD TSIAQLFAEN GNLGINVTIS MC
Experimental Info
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sequence conflicti | 173 | P → S in CAE46191 (PubMed:17974005).Curated | 1 | |
| Sequence conflicti | 245 | E → G in CAE46191 (PubMed:17974005).Curated | 1 |
Alternative sequence
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Alternative sequenceiVSP_010166 | 1 | M → MTGKATPPSLYSWRGVLFTC LPAARTRKRKEM in isoform 2. 2 Publications | 1 | |
| Alternative sequenceiVSP_029210 | 193 – 195 | LEK → DLS in isoform 3. 1 Publication | 3 | |
| Alternative sequenceiVSP_029211 | 196 – 282 | Missing in isoform 3. 1 PublicationAdd BLAST | 87 |
Sequence databases
| Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U63295 mRNA Translation: AAC12950.1 U76247 mRNA Translation: AAC51907.1 AJ400626 Genomic DNA Translation: CAC35542.1 EF026094 mRNA Translation: ABK15529.1 BX647064 mRNA Translation: CAE46191.1 BC035562 mRNA Translation: AAH35562.1 BC042550 mRNA Translation: AAH42550.1 BC044920 mRNA Translation: AAH44920.1 |
| CCDSi | CCDS10735.1 [Q8IUQ4-1] CCDS32444.1 [Q8IUQ4-2] |
| RefSeqi | NP_001006611.1, NM_001006610.1 [Q8IUQ4-2] NP_003022.3, NM_003031.3 [Q8IUQ4-1] XP_006721309.1, XM_006721246.1 [Q8IUQ4-1] XP_011521581.1, XM_011523279.1 [Q8IUQ4-1] |
| UniGenei | Hs.706828 |
Genome annotation databases
| Ensembli | ENST00000356721; ENSP00000349156; ENSG00000196470 [Q8IUQ4-2] ENST00000380006; ENSP00000369343; ENSG00000196470 [Q8IUQ4-1] ENST00000394725; ENSP00000378214; ENSG00000196470 [Q8IUQ4-1] ENST00000568007; ENSP00000456421; ENSG00000196470 [Q8IUQ4-1] |
| GeneIDi | 6477 |
| KEGGi | hsa:6477 |
| UCSCi | uc002efl.4 human [Q8IUQ4-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Entry informationi
| Entry namei | SIAH1_HUMAN | |
| Accessioni | Q8IUQ4Primary (citable) accession number: Q8IUQ4 Secondary accession number(s): A0FKF3 Q92880 | |
| Entry historyi | Integrated into UniProtKB/Swiss-Prot: | April 26, 2004 |
| Last sequence update: | April 26, 2004 | |
| Last modified: | July 18, 2018 | |
| This is version 168 of the entry and version 2 of the sequence. See complete history. | ||
| Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
| Annotation program | Chordata Protein Annotation Program | |
| Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. | |
Miscellaneousi
Keywords - Technical termi
3D-structure, Complete proteome, Reference proteomeDocuments
- Human chromosome 16
Human chromosome 16: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PATHWAY comments
Index of metabolic and biosynthesis pathways - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families
