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Protein

E3 ubiquitin-protein ligase SIAH2

Gene

SIAH2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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 (POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia. It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes. Has some overlapping function with SIAH1. Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not. Promotes monoubiquitination of SNCA.5 Publications

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 keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi138Zinc 1By similarity1
Metal bindingi145Zinc 1By similarity1
Metal bindingi157Zinc 1By similarity1
Metal bindingi161Zinc 1By similarity1
Metal bindingi168Zinc 2By similarity1
Metal bindingi175Zinc 2By similarity1
Metal bindingi187Zinc 2By similarity1
Metal bindingi192Zinc 2By similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri80 – 115RING-typePROSITE-ProRule annotationAdd BLAST36
Zinc fingeri133 – 193SIAH-typePROSITE-ProRule annotationAdd BLAST61

GO - Molecular functioni

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • axon guidance Source: Reactome
  • cell cycle Source: UniProtKB-KW
  • cellular protein catabolic process Source: MGI
  • cellular protein metabolic process Source: Reactome
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of canonical Wnt signaling pathway Source: MGI
  • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • negative regulation of extrinsic apoptotic signaling pathway Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: GO_Central
  • protein polyubiquitination Source: Reactome
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: GO_Central
  • regulation of protein ubiquitination Source: Ensembl
  • small GTPase mediated signal transduction Source: ProtInc
  • ubiquitin-dependent protein catabolic process Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Apoptosis, Cell cycle, Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000181788-MONOMER.
ReactomeiR-HSA-373752. Netrin-1 signaling.
R-HSA-5689880. Ub-specific processing proteases.
R-HSA-977225. Amyloid fiber formation.
R-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
SIGNORiO43255.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase SIAH2 (EC:6.3.2.-)
Alternative name(s):
Seven in absentia homolog 2
Short name:
Siah-2
Short name:
hSiah2
Gene namesi
Name:SIAH2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:10858. SIAH2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: ProtInc
  • cytosol Source: UniProtKB
  • early endosome Source: Ensembl
  • intracellular membrane-bounded organelle Source: HPA
  • neuronal cell body Source: Ensembl
  • neuron projection Source: Ensembl
  • nucleoplasm Source: HPA
  • nucleus Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi16S → A: Strongly reduced phosphorylation by DYRK2; when associated with A-26; A-28; A-68 and A-119. 1 Publication1
Mutagenesisi26T → A: Strongly reduced phosphorylation by DYRK2; when associated with A-16; A-28; A-68 and A-119. 1 Publication1
Mutagenesisi28S → A: Strongly reduced phosphorylation by DYRK2; when associated with A-16; A-26; A-68 and A-119. 1 Publication1
Mutagenesisi68S → A: Strongly reduced phosphorylation by DYRK2; when associated with A-16; A-26; A-28 and A-119. 1 Publication1
Mutagenesisi119T → A: Strongly reduced phosphorylation by DYRK2; when associated with A-16; A-26; A-28 and A-68. 1 Publication1

Organism-specific databases

DisGeNETi6478.
OpenTargetsiENSG00000181788.
PharmGKBiPA35760.

Polymorphism and mutation databases

BioMutaiSIAH2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000561681 – 324E3 ubiquitin-protein ligase SIAH2Add BLAST324

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei6PhosphoserineCombined sources1
Modified residuei16Phosphoserine; by DYRK21 Publication1
Modified residuei26Phosphothreonine; by DYRK21 Publication1
Modified residuei28Phosphoserine; by DYRK2 and MAPK141 Publication1
Modified residuei68Phosphoserine; by DYRK21 Publication1
Modified residuei119Phosphothreonine; by DYRK21 Publication1

Post-translational modificationi

Phosphorylated at Ser-28 by MAPK14, which mediates the degradation by the proteasome of EGLN3 (By similarity). Phosphorylated at Ser-28 by DYRK2; this increases the ubiquitin ligase activity and promotes degradation of EGLN3.By similarity1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiO43255.
PaxDbiO43255.
PeptideAtlasiO43255.
PRIDEiO43255.

PTM databases

iPTMnetiO43255.
PhosphoSitePlusiO43255.

Expressioni

Tissue specificityi

Widely expressed at low level.1 Publication

Gene expression databases

BgeeiENSG00000181788.
CleanExiHS_SIAH2.
ExpressionAtlasiO43255. baseline and differential.
GenevisibleiO43255. HS.

Organism-specific databases

HPAiHPA061293.

Interactioni

Subunit structurei

Homodimer. Interacts with UBE2E2. Interacts with PEG3 (By similarity). Interacts with VAV1, without mediating its ubiquitin-mediated degradation. Interacts with CACYBP/SIP. Probable component of some large E3 complex possibly composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with PEG10, which may inhibit its activity. Interacts with EGLN2 and SNCAIP. Interacts with DYRK2.By similarity7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
OPRM1P353723EBI-948141,EBI-2624570
SH3RF1Q7Z6J02EBI-948141,EBI-311339

Protein-protein interaction databases

BioGridi112373. 68 interactors.
DIPiDIP-41874N.
IntActiO43255. 16 interactors.
MINTiMINT-200601.
STRINGi9606.ENSP00000322457.

Structurei

Secondary structure

1324
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi135 – 137Combined sources3
Helixi141 – 143Combined sources3
Beta strandi148 – 150Combined sources3
Turni151 – 153Combined sources3
Helixi154 – 160Combined sources7
Helixi181 – 183Combined sources3
Helixi184 – 191Combined sources8
Beta strandi196 – 207Combined sources12
Beta strandi217 – 224Combined sources8
Beta strandi227 – 239Combined sources13
Beta strandi242 – 253Combined sources12
Helixi255 – 258Combined sources4
Beta strandi262 – 269Combined sources8
Beta strandi272 – 278Combined sources7
Helixi283 – 285Combined sources3
Helixi288 – 292Combined sources5
Beta strandi296 – 300Combined sources5
Helixi301 – 307Combined sources7
Beta strandi312 – 320Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5H9MX-ray1.76A/B131-321[»]
ProteinModelPortaliO43255.
SMRiO43255.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni130 – 322SBDAdd BLAST193

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).By similarity

Sequence similaritiesi

Belongs to the SINA (Seven in absentia) family.Curated
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation
Contains 1 SIAH-type zinc finger.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri80 – 115RING-typePROSITE-ProRule annotationAdd BLAST36
Zinc fingeri133 – 193SIAH-typePROSITE-ProRule annotationAdd BLAST61

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3002. Eukaryota.
ENOG410XVP0. LUCA.
GeneTreeiENSGT00390000005434.
HOGENOMiHOG000231487.
HOVERGENiHBG055701.
InParanoidiO43255.
KOiK08742.
OMAiKQCRQKL.
OrthoDBiEOG091G0BPY.
PhylomeDBiO43255.
TreeFamiTF312976.

Family and domain databases

Gene3Di2.60.210.10. 1 hit.
3.30.40.10. 1 hit.
3.90.890.10. 1 hit.
InterProiIPR018121. 7-in-absentia-prot_TRAF-dom.
IPR013323. SIAH-type.
IPR004162. SINA-like.
IPR008974. TRAF-like.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR013010. Znf_SIAH.
[Graphical view]
PANTHERiPTHR10315. PTHR10315. 1 hit.
PfamiPF03145. Sina. 1 hit.
[Graphical view]
SUPFAMiSSF49599. SSF49599. 1 hit.
PROSITEiPS50089. ZF_RING_2. 1 hit.
PS51081. ZF_SIAH. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O43255-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSRPSSTGPS ANKPCSKQPP PQPQHTPSPA APPAAATISA AGPGSSAVPA
60 70 80 90 100
AAAVISGPGG GGGAGPVSPQ HHELTSLFEC PVCFDYVLPP ILQCQAGHLV
110 120 130 140 150
CNQCRQKLSC CPTCRGALTP SIRNLAMEKV ASAVLFPCKY ATTGCSLTLH
160 170 180 190 200
HTEKPEHEDI CEYRPYSCPC PGASCKWQGS LEAVMSHLMH AHKSITTLQG
210 220 230 240 250
EDIVFLATDI NLPGAVDWVM MQSCFGHHFM LVLEKQEKYE GHQQFFAIVL
260 270 280 290 300
LIGTRKQAEN FAYRLELNGN RRRLTWEATP RSIHDGVAAA IMNSDCLVFD
310 320
TAIAHLFADN GNLGINVTIS TCCP
Length:324
Mass (Da):34,615
Last modified:June 1, 1998 - v1
Checksum:i2D5DD845666EC924
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti200G → E in AAC51908 (PubMed:9403064).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U76248 mRNA. Translation: AAC51908.1.
Y15268 mRNA. Translation: CAA75557.1.
BC013082 mRNA. Translation: AAH13082.1.
CCDSiCCDS3152.1.
RefSeqiNP_005058.3. NM_005067.5.
UniGeneiHs.477959.
Hs.692394.

Genome annotation databases

EnsembliENST00000312960; ENSP00000322457; ENSG00000181788.
GeneIDi6478.
KEGGihsa:6478.
UCSCiuc003eyi.4. human.

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U76248 mRNA. Translation: AAC51908.1.
Y15268 mRNA. Translation: CAA75557.1.
BC013082 mRNA. Translation: AAH13082.1.
CCDSiCCDS3152.1.
RefSeqiNP_005058.3. NM_005067.5.
UniGeneiHs.477959.
Hs.692394.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5H9MX-ray1.76A/B131-321[»]
ProteinModelPortaliO43255.
SMRiO43255.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112373. 68 interactors.
DIPiDIP-41874N.
IntActiO43255. 16 interactors.
MINTiMINT-200601.
STRINGi9606.ENSP00000322457.

PTM databases

iPTMnetiO43255.
PhosphoSitePlusiO43255.

Polymorphism and mutation databases

BioMutaiSIAH2.

Proteomic databases

MaxQBiO43255.
PaxDbiO43255.
PeptideAtlasiO43255.
PRIDEiO43255.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000312960; ENSP00000322457; ENSG00000181788.
GeneIDi6478.
KEGGihsa:6478.
UCSCiuc003eyi.4. human.

Organism-specific databases

CTDi6478.
DisGeNETi6478.
GeneCardsiSIAH2.
H-InvDBHIX0163461.
HGNCiHGNC:10858. SIAH2.
HPAiHPA061293.
MIMi602213. gene.
neXtProtiNX_O43255.
OpenTargetsiENSG00000181788.
PharmGKBiPA35760.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3002. Eukaryota.
ENOG410XVP0. LUCA.
GeneTreeiENSGT00390000005434.
HOGENOMiHOG000231487.
HOVERGENiHBG055701.
InParanoidiO43255.
KOiK08742.
OMAiKQCRQKL.
OrthoDBiEOG091G0BPY.
PhylomeDBiO43255.
TreeFamiTF312976.

Enzyme and pathway databases

UniPathwayiUPA00143.
BioCyciZFISH:ENSG00000181788-MONOMER.
ReactomeiR-HSA-373752. Netrin-1 signaling.
R-HSA-5689880. Ub-specific processing proteases.
R-HSA-977225. Amyloid fiber formation.
R-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
SIGNORiO43255.

Miscellaneous databases

ChiTaRSiSIAH2. human.
GeneWikiiSIAH2.
GenomeRNAii6478.
PROiO43255.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000181788.
CleanExiHS_SIAH2.
ExpressionAtlasiO43255. baseline and differential.
GenevisibleiO43255. HS.

Family and domain databases

Gene3Di2.60.210.10. 1 hit.
3.30.40.10. 1 hit.
3.90.890.10. 1 hit.
InterProiIPR018121. 7-in-absentia-prot_TRAF-dom.
IPR013323. SIAH-type.
IPR004162. SINA-like.
IPR008974. TRAF-like.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR013010. Znf_SIAH.
[Graphical view]
PANTHERiPTHR10315. PTHR10315. 1 hit.
PfamiPF03145. Sina. 1 hit.
[Graphical view]
SUPFAMiSSF49599. SSF49599. 1 hit.
PROSITEiPS50089. ZF_RING_2. 1 hit.
PS51081. ZF_SIAH. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSIAH2_HUMAN
AccessioniPrimary (citable) accession number: O43255
Secondary accession number(s): O43270
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 26, 2004
Last sequence update: June 1, 1998
Last modified: November 2, 2016
This is version 151 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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 proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.