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Protein

E3 ubiquitin-protein ligase ARIH2

Gene

ARIH2

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

Functioni

E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:16118314, PubMed:17646546, PubMed:19340006, PubMed:24076655). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-5-RING ubiquitin ligase complex (ECS complex, also named CRL5 complex) and initiating ubiquitination of ECS substrates: associates with ECS complex and specifically mediates addition of the first ubiquitin on ECS targets (By similarity). The initial ubiquitin is then elongated (By similarity). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated form of the ECS complex (PubMed:24076655). Mediates 'Lys-6', 'Lys-48'-and 'Lys-63'-linked polyubiquitination (PubMed:16118314, PubMed:17646546, PubMed:19340006). May play a role in myelopoiesis (PubMed:19340006).By similarity4 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.3 Publications

Enzyme regulationi

Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity (By similarity). Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1 (PubMed:24076655).By similarity1 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 bindingi139Zinc 1By similarity1
Metal bindingi142Zinc 1By similarity1
Metal bindingi156Zinc 2By similarity1
Metal bindingi158Zinc 2; via pros nitrogenBy similarity1
Metal bindingi161Zinc 1By similarity1
Metal bindingi164Zinc 1By similarity1
Metal bindingi183Zinc 2By similarity1
Metal bindingi188Zinc 2By similarity1
Metal bindingi228Zinc 3By similarity1
Metal bindingi233Zinc 3By similarity1
Metal bindingi249Zinc 3By similarity1
Metal bindingi252Zinc 3By similarity1
Metal bindingi257Zinc 4By similarity1
Metal bindingi260Zinc 4By similarity1
Metal bindingi265Zinc 4; via tele nitrogenBy similarity1
Metal bindingi270Zinc 4By similarity1
Metal bindingi297Zinc 5By similarity1
Metal bindingi300Zinc 5By similarity1
Active sitei3101 Publication1
Metal bindingi315Zinc 5By similarity1
Metal bindingi318Zinc 5By similarity1
Metal bindingi323Zinc 6By similarity1
Metal bindingi326Zinc 6By similarity1
Metal bindingi333Zinc 6; via tele nitrogenBy similarity1
Metal bindingi340Zinc 6By similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri139 – 188RING-type 1; atypicalPROSITE-ProRule annotationAdd BLAST50
Zinc fingeri208 – 270IBR-typeAdd BLAST63
Zinc fingeri297 – 326RING-type 2PROSITE-ProRule annotationAdd BLAST30

GO - Molecular functioni

  • ubiquitin conjugating enzyme binding Source: UniProtKB
  • ubiquitin protein ligase activity Source: GO_Central
  • ubiquitin-protein transferase activity Source: UniProtKB
  • zinc ion binding Source: ProtInc

GO - Biological processi

  • developmental cell growth Source: UniProtKB
  • hematopoietic stem cell proliferation Source: UniProtKB
  • multicellular organism development Source: ProtInc
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: GO_Central
  • positive regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • protein K48-linked ubiquitination Source: UniProtKB
  • protein K63-linked ubiquitination Source: UniProtKB
  • protein polyubiquitination Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Transferase

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000177479-MONOMER.
ReactomeiR-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase ARIH2 (EC:2.3.2.-3 Publications)
Short name:
ARI-2
Short name:
Protein ariadne-2 homolog
Alternative name(s):
RING-type E3 ubiquitin transferase ARIH2Curated
Triad1 protein1 Publication
Gene namesi
Name:ARIH2
Synonyms:ARI2, TRIAD11 Publication
ORF Names:HT005
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:690. ARIH2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • nucleus Source: UniProtKB
  • ubiquitin ligase complex Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi84 – 86LKV → AKA: Reduced interaction with neddylated CUL5; when associated with A-100. 1 Publication3
Mutagenesisi100W → A: Reduced interaction with neddylated CUL5; when associated with 84-A--A-86. 1 Publication1
Mutagenesisi158H → A: Loss of effect in myelopoiesis. Abolishes interaction with UBE2L3. 2 Publications1
Mutagenesisi161C → A: Loss of effect in myelopoiesis. 1 Publication1
Mutagenesisi257C → A: Does not affect interaction with UBE2L3. 1 Publication1
Mutagenesisi300C → A: Does not affect interaction with UBE2L3. 1 Publication1
Mutagenesisi310C → A: Abolishes E3 ubiquitin-protein ligase activity. 1 Publication1

Organism-specific databases

DisGeNETi10425.
OpenTargetsiENSG00000177479.
PharmGKBiPA24983.

Polymorphism and mutation databases

BioMutaiARIH2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000557551 – 493E3 ubiquitin-protein ligase ARIH2Add BLAST493

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei353PhosphoserineCombined sources1

Post-translational modificationi

Ubiquitinated. Ubiquitination promotes proteasomal degradation.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO95376.
MaxQBiO95376.
PaxDbiO95376.
PeptideAtlasiO95376.
PRIDEiO95376.

PTM databases

iPTMnetiO95376.
PhosphoSitePlusiO95376.

Expressioni

Tissue specificityi

Widely expressed with higher expression in granulocytes.1 Publication

Inductioni

Up-regulated by all-trans retinoic acid (ATRA). Up-regulated during differentiation of immature blood cells toward monocytes and granulocytes.1 Publication

Gene expression databases

BgeeiENSG00000177479.
CleanExiHS_ARIH2.
ExpressionAtlasiO95376. baseline and differential.
GenevisibleiO95376. HS.

Organism-specific databases

HPAiHPA069715.

Interactioni

Subunit structurei

Interacts (via RING-type zinc finger 1) with UBE2L3 (PubMed:16118314, PubMed:19340006, PubMed:24076655). Interacts (via RING-type zinc finger 2) with UBE2N (PubMed:19340006). Interacts with neddylated CUL5 (PubMed:24076655). Interacts (via RING-type 2) with GFI1B (PubMed:17646546). Interacts with GFI1; prevents its ubiquitination and proteasomal degradation (PubMed:17646546).4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
BUB1O436833EBI-711158,EBI-748936
CUL5Q9303412EBI-711158,EBI-1057139
RELQ048643EBI-711158,EBI-307352
TP53P046375EBI-711158,EBI-366083
UBE2L3P6803612EBI-711158,EBI-711173
UBE2L6O1493311EBI-711158,EBI-2129974
UGP2Q168516EBI-711158,EBI-743729

GO - Molecular functioni

  • ubiquitin conjugating enzyme binding Source: UniProtKB

Protein-protein interaction databases

BioGridi115694. 70 interactors.
IntActiO95376. 48 interactors.
MINTiMINT-1376284.
STRINGi9606.ENSP00000348769.

Structurei

3D structure databases

ProteinModelPortaliO95376.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni65 – 112UBA-likeBy similarityAdd BLAST48
Regioni359 – 493Ariadne domainBy similarityAdd BLAST135

Domaini

Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING-type zinc finger, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved active site Cys residue in the second RING-type zinc finger. The active site probably forms a thioester intermediate with ubiquitin taken from the active-site cysteine of the E2 before ultimately transferring it to a Lys residue on the substrate.By similarity
The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site.By similarity

Sequence similaritiesi

Belongs to the RBR family. Ariadne subfamily.Curated
Contains 1 IBR-type zinc finger.Curated
Contains 2 RING-type zinc fingers.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri139 – 188RING-type 1; atypicalPROSITE-ProRule annotationAdd BLAST50
Zinc fingeri208 – 270IBR-typeAdd BLAST63
Zinc fingeri297 – 326RING-type 2PROSITE-ProRule annotationAdd BLAST30

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG1815. Eukaryota.
ENOG410XP9Y. LUCA.
GeneTreeiENSGT00840000129790.
HOGENOMiHOG000216611.
HOVERGENiHBG018737.
InParanoidiO95376.
KOiK11969.
OMAiTGVGISC.
OrthoDBiEOG091G06CV.
PhylomeDBiO95376.
TreeFamiTF300805.

Family and domain databases

Gene3Di3.30.40.10. 3 hits.
InterProiIPR031127. E3_UB_ligase_RBR.
IPR002867. IBR_dom.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR11685. PTHR11685. 1 hit.
PfamiPF01485. IBR. 2 hits.
[Graphical view]
SMARTiSM00647. IBR. 2 hits.
SM00184. RING. 2 hits.
[Graphical view]
PROSITEiPS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O95376-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSVDMNSQGS DSNEEDYDPN CEEEEEEEED DPGDIEDYYV GVASDVEQQG
60 70 80 90 100
ADAFDPEEYQ FTCLTYKESE GALNEHMTSL ASVLKVSHSV AKLILVNFHW
110 120 130 140 150
QVSEILDRYK SNSAQLLVEA RVQPNPSKHV PTSHPPHHCA VCMQFVRKEN
160 170 180 190 200
LLSLACQHQF CRSCWEQHCS VLVKDGVGVG VSCMAQDCPL RTPEDFVFPL
210 220 230 240 250
LPNEELREKY RRYLFRDYVE SHYQLQLCPG ADCPMVIRVQ EPRARRVQCN
260 270 280 290 300
RCNEVFCFKC RQMYHAPTDC ATIRKWLTKC ADDSETANYI SAHTKDCPKC
310 320 330 340 350
NICIEKNGGC NHMQCSKCKH DFCWMCLGDW KTHGSEYYEC SRYKENPDIV
360 370 380 390 400
NQSQQAQARE ALKKYLFYFE RWENHNKSLQ LEAQTYQRIH EKIQERVMNN
410 420 430 440 450
LGTWIDWQYL QNAAKLLAKC RYTLQYTYPY AYYMESGPRK KLFEYQQAQL
460 470 480 490
EAEIENLSWK VERADSYDRG DLENQMHIAE QRRRTLLKDF HDT
Length:493
Mass (Da):57,819
Last modified:May 1, 1999 - v1
Checksum:i30AFFDD327B51013
GO

Sequence cautioni

The sequence AAG09696 differs from that shown. Reason: Frameshift at several positions.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti280 – 281CA → LQ in CAA10276 (PubMed:10880484).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05410524E → K.Corresponds to variant rs11507dbSNPEnsembl.1
Natural variantiVAR_05410629E → D.Corresponds to variant rs34221642dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF099149 mRNA. Translation: AAC82469.1.
AJ130978 mRNA. Translation: CAA10276.1.
AF183427 mRNA. Translation: AAG09696.1. Frameshift.
BC000422 mRNA. Translation: AAH00422.1.
CCDSiCCDS2780.1.
RefSeqiNP_001304262.1. NM_001317333.1.
NP_001304263.1. NM_001317334.1.
NP_006312.1. NM_006321.3.
XP_016861020.1. XM_017005531.1.
XP_016861021.1. XM_017005532.1.
UniGeneiHs.633601.

Genome annotation databases

EnsembliENST00000356401; ENSP00000348769; ENSG00000177479.
ENST00000449376; ENSP00000403222; ENSG00000177479.
GeneIDi10425.
KEGGihsa:10425.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF099149 mRNA. Translation: AAC82469.1.
AJ130978 mRNA. Translation: CAA10276.1.
AF183427 mRNA. Translation: AAG09696.1. Frameshift.
BC000422 mRNA. Translation: AAH00422.1.
CCDSiCCDS2780.1.
RefSeqiNP_001304262.1. NM_001317333.1.
NP_001304263.1. NM_001317334.1.
NP_006312.1. NM_006321.3.
XP_016861020.1. XM_017005531.1.
XP_016861021.1. XM_017005532.1.
UniGeneiHs.633601.

3D structure databases

ProteinModelPortaliO95376.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115694. 70 interactors.
IntActiO95376. 48 interactors.
MINTiMINT-1376284.
STRINGi9606.ENSP00000348769.

PTM databases

iPTMnetiO95376.
PhosphoSitePlusiO95376.

Polymorphism and mutation databases

BioMutaiARIH2.

Proteomic databases

EPDiO95376.
MaxQBiO95376.
PaxDbiO95376.
PeptideAtlasiO95376.
PRIDEiO95376.

Protocols and materials databases

DNASUi10425.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000356401; ENSP00000348769; ENSG00000177479.
ENST00000449376; ENSP00000403222; ENSG00000177479.
GeneIDi10425.
KEGGihsa:10425.

Organism-specific databases

CTDi10425.
DisGeNETi10425.
GeneCardsiARIH2.
HGNCiHGNC:690. ARIH2.
HPAiHPA069715.
MIMi605615. gene.
neXtProtiNX_O95376.
OpenTargetsiENSG00000177479.
PharmGKBiPA24983.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1815. Eukaryota.
ENOG410XP9Y. LUCA.
GeneTreeiENSGT00840000129790.
HOGENOMiHOG000216611.
HOVERGENiHBG018737.
InParanoidiO95376.
KOiK11969.
OMAiTGVGISC.
OrthoDBiEOG091G06CV.
PhylomeDBiO95376.
TreeFamiTF300805.

Enzyme and pathway databases

UniPathwayiUPA00143.
BioCyciZFISH:ENSG00000177479-MONOMER.
ReactomeiR-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.

Miscellaneous databases

ChiTaRSiARIH2. human.
GeneWikiiARIH2.
GenomeRNAii10425.
PROiO95376.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000177479.
CleanExiHS_ARIH2.
ExpressionAtlasiO95376. baseline and differential.
GenevisibleiO95376. HS.

Family and domain databases

Gene3Di3.30.40.10. 3 hits.
InterProiIPR031127. E3_UB_ligase_RBR.
IPR002867. IBR_dom.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR11685. PTHR11685. 1 hit.
PfamiPF01485. IBR. 2 hits.
[Graphical view]
SMARTiSM00647. IBR. 2 hits.
SM00184. RING. 2 hits.
[Graphical view]
PROSITEiPS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiARI2_HUMAN
AccessioniPrimary (citable) accession number: O95376
Secondary accession number(s): Q9HBZ6, Q9UEM9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: November 30, 2016
This is version 150 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. 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.