O00257 (CBX4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 SUMO-protein ligase CBX4
EC=6.3.2.-

Alternative name(s):
Chromobox protein homolog 4
Polycomb 2 homolog
Short name=Pc2
Short name=hPc2

Gene names

Name:

CBX4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	560 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E3 SUMO-protein ligase which facilitates SUMO1 conjugation by UBE2I. Involved in the sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression. Ref.9 Ref.11 Ref.12 Ref.17 Ref.18 Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Ref.9 Ref.11 Ref.12 Ref.17 Ref.18
Pathway	Protein modification; protein sumoylation.
Subunit structure	Interacts with histone H3-K9Me3. Interacts with CHTOP By similarity. Component of a PRC1-like complex. Self-associates. Interacts with SUV39H1 and HIPK2. Interacts with CSNK2B. Ref.7 Ref.8 Ref.12 Ref.14 Ref.17
Subcellular location	Nucleus. Nucleus speckle Ref.2 Ref.9 Ref.12 Ref.17.
Tissue specificity	Ubiquitous.
Domain	The polyhistidine repeat may act as a targeting signal to nuclear speckles (Ref.2).
Post-translational modification	Phosphorylated on Thr-497 by HIPK2 upon DNA damage. This phosphorylation stimulates E3 SUMO-protein ligase activity and promotes sumoylation on Lys-494, as well as sumoylation of other target proteins, such as HNRNPK. Ref.12
Miscellaneous	The human orthologs of the Drosophila Polycomb group protein Pc are CBX2, CBX4, CBX6, CBX7 and CBX8. These show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purified in Ref.8 probably presents a mixture of different complexes containing different Polycomb group proteins.
Sequence similarities	Contains 1 chromo domain.
Sequence caution	The sequence AAH14967.1 differs from that shown. Reason: Aberrant splicing.

Ontologies

Keywords
Biological process	Transcription Transcription regulation Ubl conjugation pathway
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Molecular function	Chromatin regulator Ligase Repressor
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	chromatin modification Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of apoptotic process Traceable author statement Ref.1. Source: ProtInc negative regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype Ref.17. Source: UniProtKB protein sumoylation Inferred from electronic annotation. Source: UniProtKB-UniPathway transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	Golgi apparatus Inferred from direct assay. Source: HPA PRC1 complex Inferred from direct assay Ref.8Ref.14. Source: UniProtKB nuclear speck Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	SUMO binding Inferred from direct assay PubMed 20176810. Source: MGI chromatin binding Inferred from electronic annotation. Source: Compara ligase activity Inferred from electronic annotation. Source: UniProtKB-KW single-stranded RNA binding Inferred from electronic annotation. Source: Compara transcription corepressor activity Traceable author statement Ref.1. Source: ProtInc transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BMI1	P35226	2	EBI-4392727,EBI-2341576
CSNK2A1	P68400	2	EBI-4392727,EBI-347804
CSNK2B	P67870	2	EBI-4392727,EBI-348169
PCGF6	Q9BYE7	2	EBI-4392727,EBI-1048026
RNF2	Q99496	2	EBI-4392727,EBI-722416
YWHAB	P31946	2	EBI-722425,EBI-359815
YWHAE	P62258	2	EBI-4392727,EBI-356498
YWHAZ	P63104	2	EBI-4392727,EBI-347088

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O00257-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O00257-3)

The sequence of this isoform differs from the canonical sequence as follows:
     127-396: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 560

560

E3 SUMO-protein ligase CBX4

PRO_0000080206

Regions

Domain

11 – 69

59

Chromo

Region

1 – 539

539

Interaction with BMI1

Region

540 – 560

21

Interaction with RNF2

Compositional bias

378 – 400

23

His-rich

Compositional bias

389 – 400

12

Poly-His

Compositional bias

499 – 510

12

Poly-Ala

Amino acid modifications

Modified residue

149

1

N6-acetyllysine Ref.15

Modified residue

349

1

Phosphoserine Ref.16

Cross-link

494

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.10

Natural variations

Alternative sequence

127 – 396

270

Missing in isoform 2.

VSP_041599

Experimental info

Mutagenesis

434

1

S → A: Abolishes interaction with YWHAZ and YWHAE; impairs interaction with PCGF6 and BMI1; no effect on interaction with RNF2. Ref.17

Sequence conflict

137 – 138

2

Missing in AAB80718. Ref.1

Sequence conflict

142

1

P → R in AAB80718. Ref.1

Sequence conflict

458

1

P → R in AAB80718. Ref.1

Sequence conflict

458

1

P → R in AAB62734. Ref.5

Sequence conflict

477

1

C → S in AAB80718. Ref.1

Sequence conflict

477

1

C → S in AAB62734. Ref.5

Sequence conflict

480

1

T → S in AAB80718. Ref.1

Sequence conflict

480

1

T → S in AAB62734. Ref.5

Sequence conflict

505

1

V → VAA in ACA49234. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

560

Helix Strand Turn

Details...

Beta strand

13 – 22

10

Beta strand

25 – 32

8

Helix

37 – 39

3

Beta strand

41 – 44

4

Helix

45 – 48

4

Helix

51 – 53

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 28, 2009. Version 3. Checksum: DF5C8C4C0CCB1F31	FASTA	560	61,368
	10 20 30 40 50 60 MELPAVGEHV FAVESIEKKR IRKGRVEYLV KWRGWSPKYN TWEPEENILD PRLLIAFQNR 70 80 90 100 110 120 ERQEQLMGYR KRGPKPKPLV VQVPTFARRS NVLTGLQDSS TDNRAKLDLG AQGKGQGHQY 130 140 150 160 170 180 ELNSKKHHQY QPHSKERAGK PPPPGKSGKY YYQLNSKKHH PYQPDPKMYD LQYQGGHKEA 190 200 210 220 230 240 PSPTCPDLGA KSHPPDKWAQ GAGAKGYLGA VKPLAGAAGA PGKGSEKGPP NGMMPAPKEA 250 260 270 280 290 300 VTGNGIGGKM KIVKNKNKNG RIVIVMSKYM ENGMQAVKIK SGEVAEGEAR SPSHKKRAAD 310 320 330 340 350 360 ERHPPADRTF KKAAGAEEKK VEAPPKRREE EVSGVSDPQP QDAGSRKLSP TKEAFGEQPL 370 380 390 400 410 420 QLTTKPDLLA WDPARNTHPP SHHPHPHPHH HHHHHHHHHH AVGLNLSHVR KRCLSETHGE 430 440 450 460 470 480 REPCKKRLTA RSISTPTCLG GSPAAERPAD LPPAAALPQP EVILLDSDLD EPIDLRCVKT 490 500 510 520 530 540 RSEAGEPPSS LQVKPETPAS AAVAVAAAAA PTTTAEKPPA EAQDEPAESL SEFKPFFGNI 550 560 IITDVTANCL TVTFKEYVTV
	Isoform 2 [UniParc]. Checksum: B1E71D5122A7B7FA	FASTA	290	31,987
	10 20 30 40 50 60 MELPAVGEHV FAVESIEKKR IRKGRVEYLV KWRGWSPKYN TWEPEENILD PRLLIAFQNR 70 80 90 100 110 120 ERQEQLMGYR KRGPKPKPLV VQVPTFARRS NVLTGLQDSS TDNRAKLDLG AQGKGQGHQY 130 140 150 160 170 180 ELNSKKHHHH AVGLNLSHVR KRCLSETHGE REPCKKRLTA RSISTPTCLG GSPAAERPAD 190 200 210 220 230 240 LPPAAALPQP EVILLDSDLD EPIDLRCVKT RSEAGEPPSS LQVKPETPAS AAVAVAAAAA 250 260 270 280 290 PTTTAEKPPA EAQDEPAESL SEFKPFFGNI IITDVTANCL TVTFKEYVTV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis." Satijn D.P.E., Olson D.J., van der Vlag J., Hamer K.M., Lambrechts C., Masselink H., Gunster M.J., Sewalt R.G.A.B., van Driel R., Otte A.P. Mol. Cell. Biol. 17:6076-6086(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fetal brain.
[2]	"Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment." Salichs E., Ledda A., Mularoni L., Alba M.M., de la Luna S. PLoS Genet. 5:E1000397-E1000397(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION.
[3]	"Cloning and identification of NS5ATP1-binding protein 16." Liu M., Cheng J., Wang L. Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[4]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] (ISOFORM 1). Tissue: Colon.
[6]	"RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor." Satijn D.P.E., Gunster M.J., van der Vlag J., Hamer K.M., Schul W., Alkema M.J., Saurin A.J., Freemont P.S., van Driel R., Otte A.P. Mol. Cell. Biol. 17:4105-4113(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 457-560 (ISOFORM 1).
[7]	"Selective interactions between vertebrate polycomb homologs and the SUV39H1 histone lysine methyltransferase suggest that histone H3-K9 methylation contributes to chromosomal targeting of Polycomb group proteins." Sewalt R.G.A.B., Lachner M., Vargas M., Hamer K.M., den Blaauwen J.L., Hendrix T., Melcher M., Schweizer D., Jenuwein T., Otte A.P. Mol. Cell. Biol. 22:5539-5553(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SUV39H1.
[8]	"The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans." Levine S.S., Weiss A., Erdjument-Bromage H., Shao Z., Tempst P., Kingston R.E. Mol. Cell. Biol. 22:6070-6078(2002) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN A PRC1-LIKE HPRC-H COMPLEX WITH BMI1; CBX2; CBX8; PHC1; PHC2; PHC3; RING1 AND RNF2.
[9]	"The polycomb protein Pc2 is a SUMO E3." Kagey M.H., Melhuish T.A., Wotton D. Cell 113:127-137(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUMOYLATION, SUBCELLULAR LOCATION.
[10]	"Multiple activities contribute to Pc2 E3 function." Kagey M.H., Melhuish T.A., Powers S.E., Wotton D. EMBO J. 24:108-119(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-494.
[11]	"Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin." Long J., Zuo D., Park M. J. Biol. Chem. 280:35477-35489(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2." Roscic A., Moeller A., Calzado M.A., Renner F., Wimmer V.C., Gresko E., Luedi K.S., Schmitz M.L. Mol. Cell 24:77-89(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HIPK2, SUMOYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-497.
[13]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[14]	"Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus." Maertens G.N., El Messaoudi-Aubert S., Racek T., Stock J.K., Nicholls J., Rodriguez-Niedenfuhr M., Gil J., Peters G. PLoS ONE 4:E6380-E6380(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A PRC1-LIKE COMPLEX.
[15]	"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-149, MASS SPECTROMETRY.
[16]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-349, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[17]	"Interaction proteomics analysis of polycomb proteins defines distinct PRC1 Complexes in mammalian cells." Vandamme J., Volkel P., Rosnoblet C., Le Faou P., Angrand P.O. Mol. Cell. Proteomics 0:0-0(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MASS SPECTROMETRY (ISOFORM 2), IDENTIFICATION IN A PRC1-LIKE COMPLEX, SELF-ASSOCIATION, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-434.
[18]	"DNA damage-induced heterogeneous nuclear ribonucleoprotein K SUMOylation regulates p53 transcriptional activation." Pelisch F., Pozzi B., Risso G., Munoz M.J., Srebrow A. J. Biol. Chem. 287:30789-30799(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[19]	"Solution NMR structure of the chromo domain of the chromobox protein homolog 4." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: STRUCTURE BY NMR OF 8-65.
[20]	"Crystal structure of human chromobox homolog 4 (cbx4)." Structural genomics consortium (SGC) Submitted (SEP-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.51 ANGSTROMS) OF 8-62.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF013956 mRNA. Translation: AAB80718.1.
EU439707 mRNA. Translation: ACA49234.1.
AY390430 mRNA. Translation: AAQ97596.1.
AC100791 Genomic DNA. No translation available.
BC014967 mRNA. Translation: AAH14967.1. Sequence problems.
U94344 mRNA. Translation: AAB62734.1.

IPI

IPI00010872.
IPI00218135.

RefSeq

NP_003646.2. NM_003655.2.

UniGene

Hs.743401.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2K28	NMR	-	A	8-65	[»]
3I8Z	X-ray	1.51	A	8-62	[»]

ProteinModelPortal

O00257.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42042N.

IntAct

O00257. 44 interactions.

MINT

MINT-1196265.

STRING

9606.ENSP00000269397.

PTM databases

PhosphoSite

O00257.

Proteomic databases

PaxDb

O00257.

PRIDE

O00257.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000269397; ENSP00000269397; ENSG00000141582.

GeneID

8535.

KEGG

hsa:8535.

UCSC

uc002jxe.3. human.

Organism-specific databases

CTD

8535.

GeneCards

GC17M077806.

H-InvDB

HIX0014237.

HGNC

HGNC:1554. CBX4.

HPA

HPA008228.

MIM

603079. gene.

neXtProt

NX_O00257.

PharmGKB

PA26129.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG281109.

HOGENOM

HOG000206923.

HOVERGEN

HBG005257.

InParanoid

O00257.

KO

K11452.

OMA

KWAHGAG.

OrthoDB

EOG4XPQFT.

PhylomeDB

O00257.

Enzyme and pathway databases

UniPathway

UPA00886.

Gene expression databases

ArrayExpress

O00257.

Bgee

O00257.

CleanEx

HS_CBX4.

Genevestigator

O00257.

GermOnline

ENSG00000141582. Homo sapiens.

Family and domain databases

InterPro

IPR017984. Chromo_dom_subgr.
IPR023780. Chromo_domain.
IPR000953. Chromo_domain/shadow.
IPR016197. Chromodomain-like.
IPR023779. Chromodomain_CS.
[Graphical view]

Pfam

PF00385. Chromo. 1 hit.
[Graphical view]

PRINTS

PR00504. CHROMODOMAIN.

SMART

SM00298. CHROMO. 1 hit.
[Graphical view]

SUPFAM

SSF54160. Chromodomain-like. 1 hit.

PROSITE

PS00598. CHROMO_1. 1 hit.
PS50013. CHROMO_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

CBX4. human.

EvolutionaryTrace

O00257.

GenomeRNAi

8535.

NextBio

31968.

SOURCE

Search...

Entry information

Entry name

CBX4_HUMAN

Accession

Primary (citable) accession number: O00257
Secondary accession number(s): B1PJR7, Q6TPI8, Q96C04

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 24, 2001
Last sequence update:	July 28, 2009
Last modified:	May 29, 2013
This is version 129 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.