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Q8N2W9 (PIAS4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 121. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 SUMO-protein ligase PIAS4

EC=6.3.2.-
Alternative name(s):
PIASy
Protein inhibitor of activated STAT protein 4
Protein inhibitor of activated STAT protein gamma
Short name=PIAS-gamma
Gene names
Name:PIAS4
Synonyms:PIASG
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length510 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling pathway. Involved in gene silencing. Mediates sumoylation of CEBPA, PARK7, HERC2, MYB, TCF4 and RNF168. In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations. Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.17

Pathway

Protein modification; protein sumoylation.

Subunit structure

Interacts with AR, AXIN1, GATA2, LEF1, TP53 and STAT1 (IFNG-induced). Binds to AT-rich DNA sequences, known as matrix or scaffold attachment regions (MARs/SARs) By similarity. Interacts with TICAM1. Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G1 phase. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.11 Ref.14

Subcellular location

NucleusPML body. Note: Colocalizes with SUMO1 and TCF7L2/TCF4 and LEF1 in a subset of PML (promyelocytic leukemia) nuclear bodies. Ref.4 Ref.8 Ref.12

Tissue specificity

Highly expressed in testis and, at lower levels, in spleen, prostate, ovary, colon and peripheral blood leukocytes. Ref.5

Domain

The LXXLL motif is a coregulator signature that is essential for transcriptional corepression.

Post-translational modification

Sumoylated. Lys-35 is the main site of sumoylation. Sumoylation is required for TCF4 sumoylation and transcriptional activation. Represses LEF1 transcriptional activity. SUMO1 is the preferred conjugate. Ref.12

Sequence similarities

Belongs to the PIAS family.

Contains 1 PINIT domain.

Contains 1 SAP domain.

Contains 1 SP-RING-type zinc finger.

Sequence caution

The sequence AAD45155.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
Ubl conjugation pathway
Wnt signaling pathway
   Cellular componentNucleus
   DomainZinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionLigase
Repressor
   PTMAcetylation
Isopeptide bond
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of NF-kappaB transcription factor activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from direct assay Ref.4. Source: UniProtKB

positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage

Inferred from electronic annotation. Source: Ensembl

positive regulation of keratinocyte apoptotic process

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of protein sumoylation

Inferred from direct assay PubMed 17696781. Source: UniProtKB

protein sumoylation

Inferred from mutant phenotype Ref.17. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentPML body

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoplasm

Inferred from direct assay PubMed 16816390. Source: BHF-UCL

nuclear matrix

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay Ref.4. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

SUMO ligase activity

Inferred from mutant phenotype Ref.17. Source: UniProtKB

ubiquitin protein ligase binding

Inferred from physical interaction PubMed 16816390. Source: BHF-UCL

zinc ion binding

Non-traceable author statement Ref.1. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.15
Chain2 – 510509E3 SUMO-protein ligase PIAS4
PRO_0000218982

Regions

Domain12 – 4635SAP
Domain119 – 279161PINIT
Zinc finger311 – 38878SP-RING-type
Motif20 – 245LXXLL motif
Compositional bias464 – 49229Asp/Glu-rich (acidic)

Amino acid modifications

Modified residue21N-acetylalanine Ref.15
Modified residue1141N6-acetyllysine Ref.16
Cross-link35Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.12
Cross-link128Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.12

Experimental info

Mutagenesis23 – 242LL → AA: Loss of repression of AR- and STAT1-induced transcription; no effect on AR- and STAT1-binding. Ref.4 Ref.5
Mutagenesis351K → R: Complete loss of sumoylation. No enhancement of TCF4 sumoylation. No effect on interaction with TCF4. Colocalizes with SUMO1 in nucleus but concentrated into nuclear granules. Ref.4 Ref.5 Ref.8 Ref.12
Mutagenesis1281K → R: Some loss of sumoylation. Ref.4 Ref.5 Ref.8 Ref.12
Mutagenesis3421C → A: Inhibits TCF4 sumoylation. Inhibits beta-catenin-mediated TCF7L2/TCF4 activity. No colocalization with TCF7L2/TCF4 in nuclear punctate structures; when associated with A-347. Ref.4 Ref.5
Mutagenesis3471C → A: Inhibits TCF4 sumoylation. Inhibits beta-catenin-mediated TCF7L2/TCF4 activity. No colocalization with TCF7L2/TCF4 in nuclear punctate structures; when associated with A-342. AR- and STAT1-binding. Ref.4 Ref.5
Sequence conflict1781N → K Ref.1
Sequence conflict179 – 1824SREL → FQGM Ref.1
Sequence conflict179 – 1824SREL → FQGM Ref.3
Sequence conflict4821E → G in AAH66895. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q8N2W9 [UniParc].

Last modified October 1, 2002. Version 1.
Checksum: 26AAA18246E1ACE3

FASTA51056,504
        10         20         30         40         50         60 
MAAELVEAKN MVMSFRVSDL QMLLGFVGRS KSGLKHELVT RALQLVQFDC SPELFKKIKE 

        70         80         90        100        110        120 
LYETRYAKKN SEPAPQPHRP LDPLTMHSTY DRAGAVPRTP LAGPNIDYPV LYGKYLNGLG 

       130        140        150        160        170        180 
RLPAKTLKPE VRLVKLPFFN MLDELLKPTE LVPQNNEKLQ ESPCIFALTP RQVELIRNSR 

       190        200        210        220        230        240 
ELQPGVKAVQ VVLRICYSDT SCPQEDQYPP NIAVKVNHSY CSVPGYYPSN KPGVEPKRPC 

       250        260        270        280        290        300 
RPINLTHLMY LSSATNRITV TWGNYGKSYS VALYLVRQLT SSELLQRLKT IGVKHPELCK 

       310        320        330        340        350        360 
ALVKEKLRLD PDSEIATTGV RVSLICPLVK MRLSVPCRAE TCAHLQCFDA VFYLQMNEKK 

       370        380        390        400        410        420 
PTWMCPVCDK PAPYDQLIID GLLSKILSEC EDADEIEYLV DGSWCPIRAE KERSCSPQGA 

       430        440        450        460        470        480 
ILVLGPSDAN GLLPAPSVNG SGALGSTGGG GPVGSMENGK PGADVVDLTL DSSSSSEDEE 

       490        500        510 
EEEEEEEDED EEGPRPKRRC PFQKGLVPAC 

« Hide

References

« Hide 'large scale' references
[1]"Inhibition of Stat1-mediated gene activation by PIAS1."
Liu B., Liao J., Rao X., Kushner S.A., Chung C.D., Chang D.D., Shuai K.
Proc. Natl. Acad. Sci. U.S.A. 95:10626-10631(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: B-cell.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain, Lung and Skin.
[3]"A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis."
Nelson V., Davis G.E., Maxwell S.A.
Apoptosis 6:221-234(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 10-510, INTERACTION WITH TP53.
[4]"A transcriptional corepressor of Stat1 with an essential LXXLL signature motif."
Liu B., Gross M., ten Hoeve J., Shuai K.
Proc. Natl. Acad. Sci. U.S.A. 98:3203-3207(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH STAT1, SUBCELLULAR LOCATION, MUTAGENESIS OF 23-LEU-LEU-24.
[5]"Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells."
Gross M., Liu B., Tan J.-A., French F.S., Carey M., Shuai K.
Oncogene 20:3880-3887(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AR, TISSUE SPECIFICITY, MUTAGENESIS OF 23-LEU-LEU-24.
[6]"SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling."
Rui H.L., Fan E., Zhou H.M., Xu Z., Zhang Y., Lin S.C.
J. Biol. Chem. 277:42981-42986(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AXIN1.
[7]"Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy."
Chun T.-H., Itoh H., Subramanian L., Iniguez-Lluhi J.A., Nakao K.
Circ. Res. 92:1201-1208(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GATA2.
[8]"Sumoylation is involved in beta-catenin-dependent activation of Tcf-4."
Yamamoto H., Ihara M., Matsuura Y., Kikuchi A.
EMBO J. 22:2047-2059(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SUMOYLATION OF TCF4, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-35 AND LYS-128.
[9]"Transactivation properties of c-Myb are critically dependent on two SUMO-1 acceptor sites that are conjugated in a PIASy enhanced manner."
Dahle O., Andersen T.O., Nordgaard O., Matre V., Del Sal G., Gabrielsen O.S.
Eur. J. Biochem. 270:1338-1348(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SUMOYLATION OF MYB.
[10]"A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein alpha inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3."
Subramanian L., Benson M.D., Iniguez-Lluhi J.A.
J. Biol. Chem. 278:9134-9141(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SUMOYLATION OF CEBPA.
[11]"PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis."
Zhang J., Xu L.G., Han K.J., Wei X., Shu H.B.
FEBS Lett. 570:97-101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TICAM1.
[12]"SUMO-1 modification of PIASy, an E3 ligase, is necessary for PIASy-dependent activation of Tcf-4."
Ihara M., Yamamoto H., Kikuchi A.
Mol. Cell. Biol. 25:3506-3518(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-35 AND LYS-128, FUNCTION IN SUMOYLATION OF TCF4, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-35 AND LYS-128.
[13]"Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities."
Shinbo Y., Niki T., Taira T., Ooe H., Takahashi-Niki K., Maita C., Seino C., Iguchi-Ariga S.M.M., Ariga H.
Cell Death Differ. 13:96-108(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SUMOYLATION OF PARK7.
[14]"Sumoylation delimits KLF8 transcriptional activity associated with the cell cycle regulation."
Wei H., Wang X., Gan B., Urvalek A.M., Melkoumian Z.K., Guan J.-L., Zhao J.
J. Biol. Chem. 281:16664-16671(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH KLF8.
[15]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
[16]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-114, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger."
Danielsen J.R., Povlsen L.K., Villumsen B.H., Streicher W., Nilsson J., Wikstrom M., Bekker-Jensen S., Mailand N.
J. Cell Biol. 197:179-187(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SUMOYLATION OF HERC2 AND RNF168.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF077952 mRNA. Translation: AAC36703.1.
BC010047 mRNA. Translation: AAH10047.2.
BC029874 mRNA. Translation: AAH29874.1.
BC066895 mRNA. Translation: AAH66895.1.
AF164437 mRNA. Translation: AAD45155.1. Different initiation.
RefSeqNP_056981.2. NM_015897.2.
UniGeneHs.105779.

3D structure databases

ProteinModelPortalQ8N2W9.
SMRQ8N2W9. Positions 3-66, 130-407.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119624. 87 interactions.
IntActQ8N2W9. 55 interactions.
MINTMINT-1181821.
STRING9606.ENSP00000262971.

PTM databases

PhosphoSiteQ8N2W9.

Polymorphism databases

DMDM34922831.

Proteomic databases

PaxDbQ8N2W9.
PRIDEQ8N2W9.

Protocols and materials databases

DNASU51588.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000262971; ENSP00000262971; ENSG00000105229.
GeneID51588.
KEGGhsa:51588.
UCSCuc002lzg.3. human.

Organism-specific databases

CTD51588.
GeneCardsGC19P004007.
HGNCHGNC:17002. PIAS4.
HPAHPA010598.
MIM605989. gene.
neXtProtNX_Q8N2W9.
PharmGKBPA134945903.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG125513.
HOGENOMHOG000230594.
HOVERGENHBG053598.
InParanoidQ8N2W9.
KOK16065.
OMARICYTDT.
OrthoDBEOG7HF1JB.
PhylomeDBQ8N2W9.
TreeFamTF323787.

Enzyme and pathway databases

SignaLinkQ8N2W9.
UniPathwayUPA00886.

Gene expression databases

ArrayExpressQ8N2W9.
BgeeQ8N2W9.
CleanExHS_PIAS4.
GenevestigatorQ8N2W9.

Family and domain databases

Gene3D1.10.720.30. 1 hit.
InterProIPR027224. PIAS4.
IPR023321. PINIT.
IPR003034. SAP_dom.
IPR004181. Znf_MIZ.
[Graphical view]
PANTHERPTHR10782:SF9. PTHR10782:SF9. 1 hit.
PfamPF14324. PINIT. 1 hit.
PF02891. zf-MIZ. 1 hit.
[Graphical view]
SMARTSM00513. SAP. 1 hit.
[Graphical view]
PROSITEPS51466. PINIT. 1 hit.
PS50800. SAP. 1 hit.
PS51044. ZF_SP_RING. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPIAS4. human.
GeneWikiPIAS4.
GenomeRNAi51588.
NextBio55429.
PROQ8N2W9.
SOURCESearch...

Entry information

Entry namePIAS4_HUMAN
AccessionPrimary (citable) accession number: Q8N2W9
Secondary accession number(s): O75926, Q96G19, Q9UN16
Entry history
Integrated into UniProtKB/Swiss-Prot: September 19, 2003
Last sequence update: October 1, 2002
Last modified: April 16, 2014
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM