Reviewed, UniProtKB/Swiss-Prot Q15596 (NCOA2_HUMAN)

Names and origin

Protein names

Recommended name:
    Nuclear receptor coactivator 2
      Short name=NCoA-2
Alternative name(s):
    Transcriptional intermediary factor 2
      Short name=hTIF2

Gene names

Name:	NCOA2
Synonyms:	TIF2

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	1464 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Ref.4
Subunit structure	Present in a complex containing CARM1 and EP300/P300, and interacts with CARM1 and NR3C2 By similarity. Present in a complex containing NCOA3, IKKA, IKKB, IKBKG and CREBBP. Interacts (via C-terminus) with CREBBP. Interacts with HIF1A, NCOA1, APEX and NR3C1. Interacts with CASP8AP2 and TTLL5/STAMP. Interacts with ESR1, RARA and RXRA.
Subcellular location	Nucleus.
Domain	Contains four Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors and are, at least in part, functionally redundant. Ref.4 The LLXXLXXXL motif is involved in transcriptional coactivation and CREBBP/CBP binding. Ref.4 Contains 2 C-terminal transcription activation domains (AD1 and AD2) that can function independently. Ref.4
Post-translational modification	Phosphorylated upon DNA damage, probably by ATM or ATR By similarity.
Involvement in disease	Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv8(p11;q13) generates the MYST3-NCOA2 oncogene, which consists of the N-terminus part of MYST3/MOZ and the C-terminus part of NCOA2/TIF2. MYST3-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
Sequence similarities	Belongs to the SRC/p160 nuclear receptor coactivator family. Contains 1 basic helix-loop-helix (bHLH) domain. Contains 1 PAS (PER-ARNT-SIM) domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat
Molecular function	Activator
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Non-traceable author statement. Source: UniProtKB
Molecular function	nuclear hormone receptor binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AR	P10275	1	EBI-81236,EBI-608057

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1464

1464

Nuclear receptor coactivator 2

PRO_0000094402

Regions

Domain

17 – 20

4

Helix-loop-helix motif

Domain

119 – 183

65

PAS

DNA binding

21 – 84

64

Basic motif

Region

691 – 743

53

CASP8AP2-binding By similarity

Motif

641 – 645

5

LXXLL motif 1

Motif

690 – 694

5

LXXLL motif 2

Motif

745 – 749

5

LXXLL motif 3

Motif

878 – 882

5

LXXLL motif 4

Motif

1079 – 1087

9

LLXXLXXXL motif

Compositional bias

1254 – 1260

7

Poly-Gln

Sites

Site

869 – 870

2

Breakpoint for translocation to form MYST3-NCOA2

Amino acid modifications

Modified residue

493

1

Phosphoserine Ref.10

Modified residue

699

1

Phosphoserine Ref.12

Modified residue

716

1

Phosphoserine By similarity

Natural variations

Natural variant

1282

1

M → I: dbSNP rs2228591. Ref.2

VAR_024546

Experimental info

Mutagenesis

644 – 645

2

LL → AA: By itself, does not affect nuclear receptor binding or transcriptional coactivation. Abrogates ligand-induced nuclear receptor binding and transactivation; when associated with 693-A-A-694 and 748-A-A-749.

Mutagenesis

693 – 694

2

LL → AA: By itself, does not affect nuclear receptor binding or transcriptional coactivation. Abrogates ligand-induced nuclear receptor binding and transactivation; when associated with 644-A-A-665 and 748-A-A-749.

Mutagenesis

748 – 749

2

LL → AA: By itself, does not affect nuclear receptor binding or transcriptional coactivation. Abrogates ligand-induced nuclear receptor binding and transactivation; when associated with 644-A-A-665 and 693-A-A-694.

Mutagenesis

1079 – 1083

5

LLDQL → AADQA: Reduces transcriptional coactivation and disrupts interaction with CREBBP/CBP. Ref.4

Mutagenesis

1081 – 1082

2

DQ → AA: Has little effect on transcriptional coactivation.

Secondary structure

1

.

.

.

.

.

.

.

1464

Helix Strand Turn

Details...

Helix

689 – 695

7

Helix

743 – 749

7

Helix

756 – 763

8

Sequences

	Sequence		Length	Mass (Da)
	Q15596-1 [UniParc]. Last modified May 1, 1997. Version 2. Checksum: 0A61AA5D1878304B	FASTA	1,464	159,157
	10 20 30 40 50 60 MSGMGENTSD PSRAETRKRK ECPDQLGPSP KRNTEKRNRE QENKYIEELA ELIFANFNDI 70 80 90 100 110 120 DNFNFKPDKC AILKETVKQI RQIKEQEKAA AANIDEVQKS DVSSTGQGVI DKDALGPMML 130 140 150 160 170 180 EALDGFFFVV NLEGNVVFVS ENVTQYLRYN QEELMNKSVY SILHVGDHTE FVKNLLPKSI 190 200 210 220 230 240 VNGGSWSGEP PRRNSHTFNC RMLVKPLPDS EEEGHDNQEA HQKYETMQCF AVSQPKSIKE 250 260 270 280 290 300 EGEDLQSCLI CVARRVPMKE RPVLPSSESF TTRQDLQGKI TSLDTSTMRA AMKPGWEDLV 310 320 330 340 350 360 RRCIQKFHAQ HEGESVSYAK RHHHEVLRQG LAFSQIYRFS LSDGTLVAAQ TKSKLIRSQT 370 380 390 400 410 420 TNEPQLVISL HMLHREQNVC VMNPDLTGQT MGKPLNPISS NSPAHQALCS GNPGQDMTLS 430 440 450 460 470 480 SNINFPINGP KEQMGMPMGR FGGSGGMNHV SGMQATTPQG SNYALKMNSP SQSSPGMNPG 490 500 510 520 530 540 QPTSMLSPRH RMSPGVAGSP RIPPSQFSPA GSLHSPVGVC SSTGNSHSYT NSSLNALQAL 550 560 570 580 590 600 SEGHGVSLGS SLASPDLKMG NLQNSPVNMN PPPLSKMGSL DSKDCFGLYG EPSEGTTGQA 610 620 630 640 650 660 ESSCHPGEQK ETNDPNLPPA VSSERADGQS RLHDSKGQTK LLQLLTTKSD QMEPSPLASS 670 680 690 700 710 720 LSDTNKDSTG SLPGSGSTHG TSLKEKHKIL HRLLQDSSSP VDLAKLTAEA TGKDLSQESS 730 740 750 760 770 780 STAPGSEVTI KQEPVSPKKK ENALLRYLLD KDDTKDIGLP EITPKLERLD SKTDPASNTK 790 800 810 820 830 840 LIAMKTEKEE MSFEPGDQPG SELDNLEEIL DDLQNSQLPQ LFPDTRPGAP AGSVDKQAII 850 860 870 880 890 900 NDLMQLTAEN SPVTPVGAQK TALRISQSTF NNPRPGQLGR LLPNQNLPLD ITLQSPTGAG 910 920 930 940 950 960 PFPPIRNSSP YSVIPQPGMM GNQGMIGNQG NLGNSSTGMI GNSASRPTMP SGEWAPQSSA 970 980 990 1000 1010 1020 VRVTCAATTS AMNRPVQGGM IRNPAASIPM RPSSQPGQRQ TLQSQVMNIG PSELEMNMGG 1030 1040 1050 1060 1070 1080 PQYSQQQAPP NQTAPWPESI LPIDQASFAS QNRQPFGSSP DDLLCPHPAA ESPSDEGALL 1090 1100 1110 1120 1130 1140 DQLYLALRNF DGLEEIDRAL GIPELVSQSQ AVDPEQFSSQ DSNIMLEQKA PVFPQQYASQ 1150 1160 1170 1180 1190 1200 AQMAQGSYSP MQDPNFHTMG QRPSYATLRM QPRPGLRPTG LVQNQPNQLR LQLQHRLQAQ 1210 1220 1230 1240 1250 1260 QNRQPLMNQI SNVSNVNLTL RPGVPTQAPI NAQMLAQRQR EILNQHLRQR QMHQQQQVQQ 1270 1280 1290 1300 1310 1320 RTLMMRGQGL NMTPSMVAPS GMPATMSNPR IPQANAQQFP FPPNYGISQQ PDPGFTGATT 1330 1340 1350 1360 1370 1380 PQSPLMSPRM AHTQSPMMQQ SQANPAYQAP SDINGWAQGN MGGNSMFSQQ SPPHFGQQAN 1390 1400 1410 1420 1430 1440 TSMYSNNMNI NVSMATNTGG MSSMNQMTGQ ISMTSVTSVP TSGLSSMGPE QVNDPALRGG 1450 1460 NLFPNQLPGM DMIKQEGDTT RKYC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors." Voegel J.J., Heine M.J.S., Zechel C., Chambon P., Gronemeyer H. EMBO J. 15:3667-3675(1996) [PubMed: 8670870] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[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], VARIANT ILE-1282.
[3]	"A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia." Carapeti M., Aguiar R.C.T., Goldman J.M., Cross N.C.P. Blood 91:3127-3133(1998) [PubMed: 9558366] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 870-939, CHROMOSOMAL TRANSLOCATION WITH MYST3.
[4]	"The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways." Voegel J.J., Heine M.J.S., Tini M., Vivat V., Chambon P., Gronemeyer H. EMBO J. 17:507-519(1998) [PubMed: 9430642] [Abstract] Cited for: FUNCTION, INTERACTION WITH CREBBP; ESR1; RARA AND RXRA, DOMAIN, MUTAGENESIS OF 644-LEU-LEU-645; 693-LEU-LEU-694; 748-LEU-LEU-749; 1079-LEU--LEU-1083 AND 1081-ASP-GLN-1082.
[5]	"Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex." Fryer C.J., Archer T.K. Nature 393:88-91(1998) [PubMed: 9590696] [Abstract] Cited for: INTERACTION WITH NR3C1.
[6]	"Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha." Carrero P., Okamoto K., Coumailleau P., O'Brien S., Tanaka H., Poellinger L. Mol. Cell. Biol. 20:402-415(2000) [PubMed: 10594042] [Abstract] Cited for: INTERACTION WITH HIF1A; NCOA1 AND APEX.
[7]	"Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by I kappa B kinase." Wu R.-C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J., O'Malley B.W. Mol. Cell. Biol. 22:3549-3561(2002) [PubMed: 11971985] [Abstract] Cited for: IDENTIFICATION IN A COACTIVATOR COMPLEX CONTAINING CREBBP; NCOA3; IKKA; IKKB AND IKBKG.
[8]	"MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP." Deguchi K., Ayton P.M., Carapeti M., Kutok J.L., Snyder C.S., Williams I.R., Cross N.C.P., Glass C.K., Cleary M.L., Gilliland D.G. Cancer Cell 3:259-271(2003) [PubMed: 12676584] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH MYST3.
[9]	"MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function." Kindle K.B., Troke P.J.F., Collins H.M., Matsuda S., Bossi D., Bellodi C., Kalkhoven E., Salomoni P., Pelicci P.G., Minucci S., Heery D.M. Mol. Cell. Biol. 25:988-1002(2005) [PubMed: 15657427] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH MYST3.
[10]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-493, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"STAMP, a novel predicted factor assisting TIF2 actions in glucocorticoid receptor-mediated induction and repression." He Y., Simons S.S. Jr. Mol. Cell. Biol. 27:1467-1485(2007) [PubMed: 17116691] [Abstract] Cited for: INTERACTION WITH TTLL5. Tissue: Testis.
[12]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-699, MASS SPECTROMETRY.
[13]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X97674 mRNA. Translation: CAA66263.1.
BC114383 mRNA. Translation: AAI14384.1.

IPI

IPI00018251.

RefSeq

NP_006531.1.

UniGene

Hs.446678

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GWQ	X-ray	2.45	C/D	688-696	[»]
1GWR	X-ray	2.40	C/D	742-750	[»]
1M2Z	X-ray	2.50	B/E	734-754	[»]
1MV9	X-ray	1.90	B	686-698	[»]
1MVC	X-ray	1.90	B	686-698	[»]
1MZN	X-ray	1.90	B/D/F/H	686-698	[»]
1P93	X-ray	2.70	E/F/G/H	740-751	[»]
1T63	X-ray	2.07	B	740-753	[»]
1T65	X-ray	1.66	B	686-698	[»]
1UHL	X-ray	2.90	C/D	687-696	[»]
1YOK	X-ray	2.50	B/C	740-753	[»]
1ZDT	X-ray	2.10	P/Q	741-752	[»]
1ZDU	X-ray	2.50	P/Q	741-751	[»]
1ZKY	X-ray	2.25	C/D	686-698	[»]
2AO6	X-ray	1.89	B	740-753	[»]
2B1V	X-ray	1.80	C/D	686-698	[»]
2B1Z	X-ray	1.78	C/D	686-698	[»]
2B23	X-ray	2.10	C/D	686-698	[»]
2FAI	X-ray	2.10	C/D	686-698	[»]
2G44	X-ray	2.65	C/D	686-698	[»]
2G5O	X-ray	2.30	C/D	686-698	[»]
2P15	X-ray	1.94	C/D	686-698	[»]
2P1T	X-ray	1.80	B	686-698	[»]
2P1U	X-ray	2.20	B	686-698	[»]
2P1V	X-ray	2.20	B	686-698	[»]
2Q7J	X-ray	1.90	B	740-753	[»]
2Q7L	X-ray	1.92	B	740-753	[»]
3CLD	X-ray	2.84	C/H	740-751	[»]
3DZU	X-ray	3.20	E/G	685-697	[»]
3DZY	X-ray	3.10	E/G	685-697	[»]
3E00	X-ray	3.10	E/G	685-697	[»]
3E7C	X-ray	2.15	D/H	741-751	[»]
3E94	X-ray	1.90	B	686-698	[»]

SMR

Q15596. Positions 1071-1115.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q15596. 2 interactions.

PTM databases

PhosphoSite

Q15596.

Proteomic databases

PRIDE

Q15596.

Genome annotation databases

Ensembl

ENSG00000140396. Homo sapiens. [Contig view]

GeneID

10499.

KEGG

hsa:10499.

Organism-specific databases

GeneCards

GC08M071186.

H-InvDB

HIX0007575.

HGNC

HGNC:7669. NCOA2.

MIM

601993. gene.

PharmGKB

PA31471.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q15596.

HOVERGEN

Q15596.

Enzyme and pathway databases

Pathway_Interaction_DB

ar_pathway. Coregulation of Androgen receptor activity.
hif1_tfpathway. HIF-1-alpha transcription factor network.
ar_tf_pathway. Regulation of Androgen receptor activity.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
retinoic_acid_pathway. Retinoic acid receptors-mediated signaling.

Gene expression databases

ArrayExpress

Q15596.

Bgee

Q15596.

CleanEx

HS_NCOA2.

GermOnline

ENSG00000140396. Homo sapiens.

Family and domain databases

InterPro

IPR010011. DUF1518.
IPR001092. HLH_basic.
IPR014920. Nuc_rcpt_coact_Ncoa-typ.
IPR017426. Nuclear_rcpt_coactivator.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR014935. SRC-1.
[Graphical view]

Pfam

PF07469. DUF1518. 1 hit.
PF08815. Nuc_rec_co-act. 1 hit.
PF00989. PAS. 1 hit.
PF08832. SRC-1. 1 hit.
[Graphical view]

PIRSF

PIRSF038181. Nuclear_receptor_coactivator. 1 hit.

SMART

SM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 1 hit.
[Graphical view]

PROSITE

PS50888. HLH. 1 hit.
PS50112. PAS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

39840.

SOURCE

Search...

Entry information

Entry name

NCOA2_HUMAN

Accession

Primary (citable) accession number: Q15596
Secondary accession number(s): Q14CD2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 21, 2001
Last sequence update:	May 1, 1997
Last modified:	June 16, 2009
This is version 101 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)