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Protein

E3 ubiquitin-protein ligase SIAH2

Gene

SIAH2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (GPS2, 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

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.

Activity 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

  • transcription corepressor activity Source: ProtInc
  • ubiquitin conjugating enzyme binding Source: GO_Central
  • ubiquitin protein ligase activity Source: GO_Central
  • ubiquitin-protein transferase activity Source: Reactome
  • zinc ion binding Source: InterPro

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processApoptosis, Cell cycle, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

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
UniPathwayi
UPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase SIAH2 (EC:2.3.2.27)
Alternative name(s):
RING-type E3 ubiquitin transferase SIAH2Curated
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

EuPathDBiHostDB:ENSG00000181788.3
HGNCiHGNC:10858 SIAH2
MIMi602213 gene
neXtProtiNX_O43255

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
ProteomicsDBi48838

PTM databases

iPTMnetiO43255
PhosphoSitePlusiO43255

Expressioni

Tissue specificityi

Widely expressed at low level.1 Publication

Gene expression databases

BgeeiENSG00000181788 Expressed in 217 organ(s), highest expression level in adrenal tissue
CleanExiHS_SIAH2
ExpressionAtlasiO43255 baseline and differential
GenevisibleiO43255 HS

Organism-specific databases

HPAiCAB069930
HPA061293

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi112373, 71 interactors
DIPiDIP-41874N
IntActiO43255, 22 interactors
MINTiO43255
STRINGi9606.ENSP00000322457

Structurei

Secondary structure

1324
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO43255
SMRiO43255
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni130 – 322SBDBy similarityAdd 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

Sequence similaritiesi

Belongs to the SINA (Seven in absentia) family.Curated

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
OMAiHETICNF
OrthoDBiEOG091G0BPY
PhylomeDBiO43255
TreeFamiTF312976

Family and domain databases

Gene3Di2.60.210.10, 1 hit
3.30.40.10, 1 hit
InterProiView 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
PANTHERiPTHR10315 PTHR10315, 1 hit
PfamiView protein in Pfam
PF03145 Sina, 1 hit
SUPFAMiSSF49599 SSF49599, 1 hit
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit
PS51081 ZF_SIAH, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
C9J9D7C9J9D7_HUMAN
E3 ubiquitin-protein ligase
SIAH2
83Annotation score:

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

Similar proteinsi

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, 71 interactors
DIPiDIP-41874N
IntActiO43255, 22 interactors
MINTiO43255
STRINGi9606.ENSP00000322457

PTM databases

iPTMnetiO43255
PhosphoSitePlusiO43255

Polymorphism and mutation databases

BioMutaiSIAH2

Proteomic databases

MaxQBiO43255
PaxDbiO43255
PeptideAtlasiO43255
PRIDEiO43255
ProteomicsDBi48838

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi6478
DisGeNETi6478
EuPathDBiHostDB:ENSG00000181788.3
GeneCardsiSIAH2
H-InvDBiHIX0163461
HGNCiHGNC:10858 SIAH2
HPAiCAB069930
HPA061293
MIMi602213 gene
neXtProtiNX_O43255
OpenTargetsiENSG00000181788
PharmGKBiPA35760
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

UniPathwayi
UPA00143

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
PROiPR:O43255
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000181788 Expressed in 217 organ(s), highest expression level in adrenal tissue
CleanExiHS_SIAH2
ExpressionAtlasiO43255 baseline and differential
GenevisibleiO43255 HS

Family and domain databases

Gene3Di2.60.210.10, 1 hit
3.30.40.10, 1 hit
InterProiView 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
PANTHERiPTHR10315 PTHR10315, 1 hit
PfamiView protein in Pfam
PF03145 Sina, 1 hit
SUPFAMiSSF49599 SSF49599, 1 hit
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit
PS51081 ZF_SIAH, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSIAH2_HUMAN
AccessioniPrimary (citable) accession number: O43255
Secondary accession number(s): O43270
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 26, 2004
Last sequence update: June 1, 1998
Last modified: November 7, 2018
This is version 168 of the entry and version 1 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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