Reviewed, UniProtKB/Swiss-Prot Q8N2W9 (PIAS4_HUMAN)

Names and origin

Protein names

Recommended name:
    E3 SUMO-protein ligase PIAS4
Alternative name(s):
    Protein inhibitor of activated STAT protein 4
    Protein inhibitor of activated STAT protein gamma
      Short name=PIAS-gamma
    PIASy

Gene names

Name:	PIAS4
Synonyms:	PIASG

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	510 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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 pathway, the Wnt pathway and the steroid hormone signaling pathway. Involved in gene silencing. Promotes PARK7 sumoylation. In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations. Ref.7 Ref.8 Ref.9 Ref.11 Ref.12
Pathway	Protein modification; protein sumoylation.
Subunit structure	Interacts with AR, 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.
Subcellular location	Nucleus. Note: Colocalizes with SUMO1 and TCF7L2/TCF4 and LEF1 in a subset of PML (promyelocytic leukemia) nuclear bodies. Ref.7 Ref.11 Ref.4
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 activitation. Represses LEF1 transcriptional activity. SUMO1 is the preferred conjugate. Ref.7 Ref.8 Ref.9 Ref.11 Ref.12
Sequence similarities	Belongs to the PIAS family. Contains 1 SAP domain. Contains 1 SP-RING-type zinc finger.

Ontologies

Keywords
Biological process	Transcription Transcription regulation Ubl conjugation pathway Wnt signaling pathway
Cellular component	Nucleus
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Repressor
PTM	Isopeptide bond Ubl conjugation
Gene Ontology (GO)
Biological process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW SUMO ligase activity Inferred from direct assay. Source: UniProtKB zinc ion binding Ref.1 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HTT	P42858	1	EBI-473160,EBI-466029
SUMO2	P61956	1	EBI-473160,EBI-473220
TADA3L	O75528	1	EBI-473160,EBI-473249
TP53	P04637	1	EBI-473160,EBI-366083
Tp53	P02340	2	EBI-473160,EBI-474016	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 510	510	E3 SUMO-protein ligase PIAS4		PRO_0000218982
Regions
	Domain	12 – 46	35	SAP
	Zinc finger	311 – 388	78	SP-RING-type
	Motif	20 – 24	5	LXXLL motif
	Compositional bias	464 – 492	29	Asp/Glu-rich (acidic)
Amino acid modifications
	Cross-link	35		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.11
	Cross-link	128		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.11
Experimental info
	Mutagenesis	23 – 24	2	LL → AA: Loss of repression of AR- and STAT1-induced transcription; no effect on AR- and STAT1-binding. Ref.4 Ref.5
	Mutagenesis	35	1	K → 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.7 Ref.11 Ref.4 Ref.5
	Mutagenesis	128	1	K → R: Some loss of sumoylation. Ref.7 Ref.11 Ref.4 Ref.5
	Mutagenesis	342	1	C → A: Inhibits TCF4 sumoylation. Inhibits beta-catenin-mediated TCF7L2/TCF4 activity. No colocalization with TCF7L2/TCF4 in nuclear puntuate structures; when associated with A-347. Ref.4 Ref.5
	Mutagenesis	347	1	C → A: Inhibits TCF4 sumoylation. Inhibits beta-catenin-mediated TCF7L2/TCF4 activity. No colocalization with TCF7L2/TCF4 in nuclear puntuate structures; when associated with A-342. AR- and STAT1-binding. Ref.4 Ref.5
	Sequence conflict	178	1	N → K Ref.1
	Sequence conflict	179 – 182	4	SREL → FQGM Ref.1
	Sequence conflict	179 – 182	4	SREL → FQGM Ref.3
	Sequence conflict	482	1	E → G in AAH66895. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q8N2W9-1 [UniParc]. Last modified October 1, 2002. Version 1. Checksum: 26AAA18246E1ACE3	FASTA	510	56,504
	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

References

	« Hide 'large scale' referencesShow '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: 9724754] [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: 15489334] [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: 11388671] [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: 11248056] [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: 11439351] [Abstract] Cited for: INTERACTION WITH AR, TISSUE SPECIFICITY, MUTAGENESIS OF 23-LEU-LEU-24.
[6]	"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: 12750312] [Abstract] Cited for: INTERACTION WITH GATA2.
[7]	"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: 12727872] [Abstract] Cited for: FUNCTION IN TCF4 SUMOYLATION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-35 AND LYS-128.
[8]	"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: 12631292] [Abstract] Cited for: FUNCTION IN C-MYB SUMOYLATION.
[9]	"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: 12511558] [Abstract] Cited for: FUNCTION IN CEBPA SUMOYLATION.
[10]	"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: 15251447] [Abstract] Cited for: INTERACTION WITH TICAM1.
[11]	"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: 15831457] [Abstract] Cited for: SUMOYLATION AT LYS-35 AND LYS-128, FUNCTION IN TCF4 SUMOYLATION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-35 AND LYS-128.
[12]	"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: 15976810] [Abstract] Cited for: FUNCTION IN PARK7 SUMOYLATION.
[13]	"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: 16617055] [Abstract] Cited for: INTERACTION WITH KLF8.

Cross-references

Sequence databases
EMBLGenBankDDBJ	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.
IPI	IPI00166500.
RefSeq	NP_056981.2.
UniGene	Hs.105779
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8N2W9. 24 interactions.
PTM databases
PhosphoSite	Q8N2W9.
Proteomic databases
PRIDE	Q8N2W9.
Genome annotation databases
Ensembl	ENSG00000105229. Homo sapiens. [Contig view]
GeneID	51588.
KEGG	hsa:51588.
Organism-specific databases
GeneCards	GC19P003960.
H-InvDB	HIX0014651.
HGNC	HGNC:17002. PIAS4.
HPA	HPA010598.
MIM	605989. gene.
PharmGKB	PA134945903.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q8N2W9.
HOVERGEN	Q8N2W9.
OMA	Q8N2W9. VLRICYT.
Enzyme and pathway databases
Pathway_Interaction_DB	ar_pathway. Coregulation of Androgen receptor activity. ifngpathway. IFN-gamma pathway. smad2_3pathway. Regulation of cytoplasmic and nuclear SMAD2/3 signaling. smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
Gene expression databases
ArrayExpress	Q8N2W9.
Bgee	Q8N2W9.
CleanEx	HS_PIAS4.
GermOnline	ENSG00000105229. Homo sapiens.
Family and domain databases
InterPro	IPR003034. SAP_DNA_bd. IPR004181. Znf_MIZ. [Graphical view]
Pfam	PF02037. SAP. 1 hit. PF02891. zf-MIZ. 1 hit. [Graphical view]
SMART	SM00513. SAP. 1 hit. [Graphical view]
PROSITE	PS50800. SAP. 1 hit. PS51044. ZF_SP_RING. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	55429.
SOURCE	Search...

Entry information

Entry name

PIAS4_HUMAN

Accession

Primary (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:	June 16, 2009
This is version 69 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)