Reviewed, UniProtKB/Swiss-Prot Q92993 (TIP60_HUMAN)

Names and origin

Protein names

Recommended name:
    Histone acetyltransferase HTATIP
    EC=2.3.1.48
    EC=2.3.1.-
Alternative name(s):
    60 kDa Tat interactive protein
    Tip60
    HIV-1 Tat interactive protein
    cPLA(2)-interacting protein

Gene names

Name:	HTATIP
Synonyms:	TIP60

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	513 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A. This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Directly acetylates and activates ATM. In case of HIV-1 infection, interaction with the viral Tat protein leads to HTATIP polyubiquitination and targets it to degradation.
Catalytic activity	Acetyl-CoA + histone = CoA + acetylhistone.
Subunit structure	Interacts with the cytoplasmic tail of APP By similarity. Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit HTATIP/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41 and VPS72/YL1. HTATTIP/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC and the adenovirus E1A protein. Interacts with ATM. Interacts with PHF17. Interacts with HIV-1 Tat.
Subcellular location	Nucleus. Cytoplasm › perinuclear region. Note= Upon stimulation with EDN1, it is exported from the nucleus to the perinuclear region.
Post-translational modification	Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase. Phosphorylated form has a higher activity. Ubiquitinated by MDM2, leading to its proteasome-dependent degradation.
Sequence similarities	Belongs to the MYST (SAS/MOZ) family.

Ontologies

Keywords
Biological process	Growth regulation Host-virus interaction Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Activator Acyltransferase Chromatin regulator Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	androgen receptor signaling pathway Non-traceable author statement. Source: UniProtKB chromatin assembly or disassembly Inferred from electronic annotation. Source: InterPro double-strand break repair Ref.8 Inferred from mutant phenotype. Source: UniProtKB histone acetylation Ref.8 Inferred from direct assay. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription, DNA-dependent Non-traceable author statement. Source: UniProtKB regulation of cell growth Inferred from electronic annotation. Source: UniProtKB-KW transcription from RNA polymerase II promoter Ref.1 Traceable author statement. Source: ProtInc
Cellular component	NuA4 histone acetyltransferase complex Ref.8 Inferred from direct assay. Source: UniProtKB chromatin Inferred from electronic annotation. Source: InterPro cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	androgen receptor binding Non-traceable author statement. Source: UniProtKB chromatin binding Inferred from electronic annotation. Source: InterPro histone acetyltransferase activity Inferred from electronic annotation. Source: EC transcription coactivator activity Ref.1 Non-traceable author statement. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATXN1	P54253	1	EBI-399080,EBI-930964
DLEU1	O43261	1	EBI-399080,EBI-710057
GADD45G	O95257	1	EBI-399080,EBI-448202
KIAA1377	Q9P2H0	1	EBI-399080,EBI-473176
PTPN4	P29074	1	EBI-399080,EBI-710431
TP53	P04637	1	EBI-399080,EBI-366083

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q92993-1)

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: Q92993-2)

Also known as: PLIP;

The sequence of this isoform differs from the canonical sequence as follows:
     96-147: Missing.

Isoform 3 (identifier: Q92993-3)

The sequence of this isoform differs from the canonical sequence as follows:
     4-4: V → VVSPVPGAGRREPGEVGRARGPPVADPGAALSPQ

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 513

513

Histone acetyltransferase HTATIP

PRO_0000051580

Regions

Zinc finger

261 – 283

23

C2HC-type Potential

Sites

Active site

369

1

By similarity

Amino acid modifications

Modified residue

86

1

Phosphoserine

Modified residue

90

1

Phosphoserine; by CDC2

Natural variations

Alternative sequence

4

1

V → VVSPVPGAGRREPGEVGRAR GPPVADPGAALSPQ in isoform 3.

VSP_009104

Alternative sequence

96 – 147

52

Missing in isoform 2.

VSP_007438

Experimental info

Mutagenesis

86

1

S → A: Reduces phosphorylation. Abolishes phosphorylation; when associated with A-90. Reduced activity

Mutagenesis

90

1

S → A: Reduces phosphorylation. Abolishes phosphorylation; when associated with A-86. Reduced activity

Mutagenesis

254

1

L → A: Does not affect phosphorylation; when associated with A-257

Mutagenesis

257

1

L → A: Does not affect phosphorylation; when associated with A-254

Mutagenesis

380

1

G → A: Loss of function. Does not affect phosphorylation

Sequence conflict

382

1

G → R in AAB18236 and AAB02683. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

513

Helix Strand Turn

Details...

Beta strand

12 – 15

4

Beta strand

28 – 34

7

Beta strand

37 – 39

3

Beta strand

43 – 47

5

Beta strand

56 – 58

3

Turn

60 – 62

3

Helix

65 – 67

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 16, 2003. Version 2. Checksum: 63724F5E10B957D5	FASTA	513	58,582
	10 20 30 40 50 60 MAEVGEIIEG CRLPVLRRNQ DNEDEWPLAE ILSVKDISGR KLFYVHYIDF NKRLDEWVTH 70 80 90 100 110 120 ERLDLKKIQF PKKEAKTPTK NGLPGSRPGS PEREVPASAQ ASGKTLPIPV QITLRFNLPK 130 140 150 160 170 180 EREAIPGGEP DQPLSSSSCL QPNHRSTKRK VEVVSPATPV PSETAPASVF PQNGAARRAV 190 200 210 220 230 240 AAQPGRKRKS NCLGTDEDSQ DSSDGIPSAP RMTGSLVSDR SHDDIVTRMK NIECIELGRH 250 260 270 280 290 300 RLKPWYFSPY PQELTTLPVL YLCEFCLKYG RSLKCLQRHL TKCDLRHPPG NEIYRKGTIS 310 320 330 340 350 360 FFEIDGRKNK SYSQNLCLLA KCFLDHKTLY YDTDPFLFYV MTEYDCKGFH IVGYFSKEKE 370 380 390 400 410 420 STEDYNVACI LTLPPYQRRG YGKLLIEFSY ELSKVEGKTG TPEKPLSDLG LLSYRSYWSQ 430 440 450 460 470 480 TILEILMGLK SESGERPQIT INEISEITSI KKEDVISTLQ YLNLINYYKG QYILTLSEDI 490 500 510 VDGHERAMLK RLLRIDSKCL HFTPKDWSKR GKW
	Isoform 2 (PLIP) [UniParc]. Checksum: 5A0E9324550AF246		461	53,077
	10 20 30 40 50 60 MAEVGEIIEG CRLPVLRRNQ DNEDEWPLAE ILSVKDISGR KLFYVHYIDF NKRLDEWVTH 70 80 90 100 110 120 ERLDLKKIQF PKKEAKTPTK NGLPGSRPGS PEREVKRKVE VVSPATPVPS ETAPASVFPQ 130 140 150 160 170 180 NGAARRAVAA QPGRKRKSNC LGTDEDSQDS SDGIPSAPRM TGSLVSDRSH DDIVTRMKNI 190 200 210 220 230 240 ECIELGRHRL KPWYFSPYPQ ELTTLPVLYL CEFCLKYGRS LKCLQRHLTK CDLRHPPGNE 250 260 270 280 290 300 IYRKGTISFF EIDGRKNKSY SQNLCLLAKC FLDHKTLYYD TDPFLFYVMT EYDCKGFHIV 310 320 330 340 350 360 GYFSKEKEST EDYNVACILT LPPYQRRGYG KLLIEFSYEL SKVEGKTGTP EKPLSDLGLL 370 380 390 400 410 420 SYRSYWSQTI LEILMGLKSE SGERPQITIN EISEITSIKK EDVISTLQYL NLINYYKGQY 430 440 450 460 ILTLSEDIVD GHERAMLKRL LRIDSKCLHF TPKDWSKRGK W
	Isoform 3 [UniParc]. Checksum: 0CEB1F84059D3E24		546	61,770
	10 20 30 40 50 60 MAEVVSPVPG AGRREPGEVG RARGPPVADP GAALSPQGEI IEGCRLPVLR RNQDNEDEWP 70 80 90 100 110 120 LAEILSVKDI SGRKLFYVHY IDFNKRLDEW VTHERLDLKK IQFPKKEAKT PTKNGLPGSR 130 140 150 160 170 180 PGSPEREVPA SAQASGKTLP IPVQITLRFN LPKEREAIPG GEPDQPLSSS SCLQPNHRST 190 200 210 220 230 240 KRKVEVVSPA TPVPSETAPA SVFPQNGAAR RAVAAQPGRK RKSNCLGTDE DSQDSSDGIP 250 260 270 280 290 300 SAPRMTGSLV SDRSHDDIVT RMKNIECIEL GRHRLKPWYF SPYPQELTTL PVLYLCEFCL 310 320 330 340 350 360 KYGRSLKCLQ RHLTKCDLRH PPGNEIYRKG TISFFEIDGR KNKSYSQNLC LLAKCFLDHK 370 380 390 400 410 420 TLYYDTDPFL FYVMTEYDCK GFHIVGYFSK EKESTEDYNV ACILTLPPYQ RRGYGKLLIE 430 440 450 460 470 480 FSYELSKVEG KTGTPEKPLS DLGLLSYRSY WSQTILEILM GLKSESGERP QITINEISEI 490 500 510 520 530 540 TSIKKEDVIS TLQYLNLINY YKGQYILTLS EDIVDGHERA MLKRLLRIDS KCLHFTPKDW SKRGKW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator." Kamine J., Elangovan B., Subramanian T., Coleman D., Chinnadurai G. Virology 216:357-366(1996) [PubMed: 8607265] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH HIV-1 TAT. Tissue: Lymphoblast.
[2]	"PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production." Sheridan A.M., Force T., Yoon H.J., O'Leary E., Choukroun G., Taheri M.R., Bonventre J.V. Mol. Cell. Biol. 21:4470-4481(2001) [PubMed: 11416127] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH PLA2G4A, SUBCELLULAR LOCATION. Tissue: Fibroblast and Placenta.
[3]	"Identification of a larger form of the histone acetyl transferase Tip60." Legube G., Trouche D. Gene 310:161-168(2003) [PubMed: 12801643] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[4]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-513 (ISOFORM 2). Tissue: Cervix, Liver and Testis.
[6]	"Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex." Cai Y., Jin J., Tomomori-Sato C., Sato S., Sorokina I., Parmely T.J., Conaway R.C., Conaway J.W. J. Biol. Chem. 278:42733-42736(2003) [PubMed: 12963728] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-35; 150-177 AND 297-307, IDENTIFICATION IN NUA4 COMPLEX, MASS SPECTROMETRY.
[7]	"Tip60 acetylates six lysines of a specific class in core histones in vitro." Kimura A., Horikoshi M. Genes Cells 3:789-800(1998) [PubMed: 10096020] [Abstract] Cited for: ENZYME ACTIVITY IN VITRO.
[8]	"Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis." Ikura T., Ogryzko V.V., Grigoriev M., Groisman R., Wang J., Horikoshi M., Scully R., Qin J., Nakatani Y. Cell 102:463-473(2000) [PubMed: 10966108] [Abstract] Cited for: IDENTIFICATION IN THE NUA4 COMPLEX, MASS SPECTROMETRY.
[9]	"Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling." Lee H.-J., Chun M., Kandror K.V. J. Biol. Chem. 276:16597-16600(2001) [PubMed: 11262386] [Abstract] Cited for: INTERACTION WITH EDNRA.
[10]	"Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation." Legube G., Linares L.K., Lemercier C., Scheffner M., Khochbin S., Trouche D. EMBO J. 21:1704-1712(2002) [PubMed: 11927554] [Abstract] Cited for: UBIQUITINATION.
[11]	"MYC recruits the TIP60 histone acetyltransferase complex to chromatin." Frank S.R., Parisi T., Taubert S., Fernandez P., Fuchs M., Chan H.M., Livingston D.M., Amati B. EMBO Rep. 4:575-580(2003) [PubMed: 12776177] [Abstract] Cited for: ROLE IN MYC-DEPENDENT TRANSCRIPTION.
[12]	"Tip60 acetyltransferase activity is controlled by phosphorylation." Lemercier C., Legube G., Caron C., Louwagie M., Garin J., Trouche D., Khochbin S. J. Biol. Chem. 278:4713-4718(2003) [PubMed: 12468530] [Abstract] Cited for: PHOSPHORYLATION AT SER-86 AND SER-90, MUTAGENESIS OF SER-86; SER-90; LEU-254; LEU-257 AND GLY-380.
[13]	"Tip60 is a co-repressor for STAT3." Xiao H., Chung J., Kao H.-Y., Yang Y.-C. J. Biol. Chem. 278:11197-11204(2003) [PubMed: 12551922] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH HDAC7.
[14]	"The highly conserved and multifunctional NuA4 HAT complex." Doyon Y., Cote J. Curr. Opin. Genet. Dev. 14:147-154(2004) [PubMed: 15196461] [Abstract] Cited for: REVIEW ON NUA4 COMPLEX.
[15]	"Role of the histone acetyl transferase Tip60 in the p53 pathway." Legube G., Linares L.K., Tyteca S., Caron C., Scheffner M., Chevillard-Briet M., Trouche D. J. Biol. Chem. 279:44825-44833(2004) [PubMed: 15310756] [Abstract] Cited for: ROLE IN TP53-DEPENDENT TRANSCRIPTION.
[16]	"von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity." Panchenko M.V., Zhou M.I., Cohen H.T. J. Biol. Chem. 279:56032-56041(2004) [PubMed: 15502158] [Abstract] Cited for: INTERACTION WITH PHF17.
[17]	"E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1." Taubert S., Gorrini C., Frank S.R., Parisi T., Fuchs M., Chan H.M., Livingston D.M., Amati B. Mol. Cell. Biol. 24:4546-4556(2004) [PubMed: 15121871] [Abstract] Cited for: ROLE IN E2F1-DEPENDENT TRANSCRIPTION.
[18]	"A large-scale RNAi screen in human cells identifies new components of the p53 pathway." Berns K., Hijmans E.M., Mullenders J., Brummelkamp T.R., Velds A., Heimerikx M., Kerkhoven R.M., Madiredjo M., Nijkamp W., Weigelt B., Agami R., Ge W., Cavet G., Linsley P.S., Beijersbergen R.L., Bernards R. Nature 428:431-437(2004) [PubMed: 15042092] [Abstract] Cited for: ROLE IN TP53-DEPENDENT TRANSCRIPTION.
[19]	"HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses." Col E., Caron C., Chable-Bessia C., Legube G., Gazzeri S., Komatsu Y., Yoshida M., Benkirane M., Trouche D., Khochbin S. EMBO J. 24:2634-2645(2005) [PubMed: 16001085] [Abstract] Cited for: INTERACTION WITH HIV-1 TAT.
[20]	"A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM." Sun Y., Jiang X., Chen S., Fernandes N., Price B.D. Proc. Natl. Acad. Sci. U.S.A. 102:13182-13187(2005) [PubMed: 16141325] [Abstract] Cited for: INTERACTION WITH ATM, FUNCTION.
[21]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-86 AND SER-90, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

U74667 mRNA. Translation: AAB18236.1.
U40989 mRNA. Translation: AAB02683.1. Different initiation.
U67734 mRNA. Translation: AAD00163.1.
AY214165 Genomic DNA. Translation: AAO21130.1.
BC000166 mRNA. Translation: AAH00166.3.
BC064912 mRNA. Translation: AAH64912.1.
BC117167 mRNA. Translation: AAI17168.1.

RefSeq

NP_006379.2.
NP_874368.1.

UniGene

Hs.528299

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2OU2	X-ray	2.30	A	227-506	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q92993.

PTM databases

PhosphoSite

Q92993.

Polymorphism databases

NIEHS-SNPs

Search...

Genome annotation databases

Ensembl

ENSG00000172977. Homo sapiens. [Contig view]

GeneID

10524.

KEGG

hsa:10524.

Organism-specific databases

H-InvDB

HIX0026169.

HGNC

HGNC:5275. HTATIP.

HPA

HPA016953.

MIM

601409. gene.

PharmGKB

PA29538.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOVERGEN

Q92993.

Gene expression databases

GermOnline

ENSG00000172977. Homo sapiens.

Family and domain databases

InterPro

IPR016181. Acyl_CoA_acyltransferase.
IPR000953. Chromodomain.
IPR002717. MOZ_SAS.
IPR011991. Wing_hlx_DNA_bd.
[Graphical view]

Gene3D

G3DSA:3.40.630.30. Acyl_CoA_acyltransferase. 1 hit.
G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit.

Pfam

PF01853. MOZ_SAS. 1 hit.
[Graphical view]

SMART

SM00298. CHROMO. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

39922.

SOURCE

Search...

Entry information

Entry name

TIP60_HUMAN

Accession

Primary (citable) accession number: Q92993
Secondary accession number(s): O95624 , Q13430, Q17RW5, Q6GSE8, Q9BWK7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	May 16, 2003
Last modified:	November 25, 2008
This is version 91 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)