Reviewed, UniProtKB/Swiss-Prot Q04207 (TF65_MOUSE)

Names and origin

Protein names

Recommended name:
    Transcription factor p65
Alternative name(s):
    Nuclear factor NF-kappa-B p65 subunit

Gene names

Name:	Rela
Synonyms:	Nfkb3

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	549 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression By similarity. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex.
Subunit structure	Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds AES and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1. Interacts with NFKBIA. Interacts with GSK3B. Interacts with NFKBIB. Interacts with NFKBIE. Interacts with NFKBIZ. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, IKBKAP and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with MTDH and PHF11 By similarity. Interacts with NFKBID. Interacts with ARRB2 By similarity. Ref.5 Ref.6 Ref.10 Ref.11
Subcellular location	Nucleus. Cytoplasm. Note: Nuclear, but also found in the cytoplasm in an inactive form complexed to an inhibitor (I-kappa-B).
Post-translational modification	Ubiquitinated, leading to its proteosomal degradation. Degradation is required for termination of NF-kappa-B response By similarity. Phosphorylation on 'Ser-534' stimulates acetylation on 'Lys-310' and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity By similarity. Ref.7 Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3. Acetylation at 'Lys-122' enhances DNA binding and impairs association with NFKBIA. Acetylation at 'Lys-310' is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation can also lower DNA-binding and results in nuclear export By similarity.
Sequence similarities	Contains 1 RHD (Rel-like) domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Ligand	DNA-binding
Molecular function	Activator
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	hair follicle development Inferred from mutant phenotype. Source: MGI liver development Inferred from mutant phenotype. Source: UniProtKB negative regulation of protein catabolic process Inferred from mutant phenotype. Source: MGI organ morphogenesis Inferred from mutant phenotype. Source: MGI positive regulation of interleukin-12 biosynthetic process Inferred from direct assay. Source: MGI response to muramyl dipeptide Inferred from direct assay. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.6 Inferred from direct assay. Source: MGI
Molecular function	RNA polymerase II transcription factor activity, enhancer binding Inferred from direct assay. Source: UniProtKB transcription activator activity Traceable author statement. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Crebbp	P45481	1	EBI-644400,EBI-296306
Hdac1	O09106	1	EBI-644400,EBI-301912
Nfkbia	Q9Z1E3	2	EBI-644400,EBI-644427
Nr4a2	Q06219	2	EBI-644400,EBI-2337255

Alternative products

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

Isoform p65 (identifier: Q04207-1)

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 p65 delta (identifier: Q04207-2)

The sequence of this isoform differs from the canonical sequence as follows:
     222-231: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 549

549

Transcription factor p65

PRO_0000205170

Regions

Domain

19 – 306

288

RHD

Motif

301 – 304

4

Nuclear localization signal Potential

Amino acid modifications

Modified residue

122

1

N6-acetyllysine; by PCAF and EP300 By similarity

Modified residue

123

1

N6-acetyllysine; by PCAF and EP300 By similarity

Modified residue

254

1

Phosphothreonine By similarity

Modified residue

276

1

Phosphoserine; by RPS6KA4 and RPS6KA5 By similarity

Modified residue

281

1

Phosphoserine By similarity

Modified residue

310

1

N6-acetyllysine By similarity

Modified residue

311

1

Phosphoserine; by PKC/PRKCZ Ref.7

Modified residue

433

1

Phosphothreonine By similarity

Modified residue

467

1

Phosphoserine; by IKKB and IKKE By similarity

Modified residue

504

1

Phosphothreonine; by CHK1 By similarity

Modified residue

527

1

Phosphoserine; by CK2 By similarity

Modified residue

534

1

Phosphoserine; by IKKB By similarity

Natural variations

Alternative sequence

222 – 231

10

Missing in isoform p65 delta.

VSP_005589

Experimental info

Mutagenesis

281

1

S → A or E: Abolishes DNA-binding and transcriptional activity. Ref.8

Sequence conflict

28

1

K → N in AAB00795. Ref.3

Sequence conflict

61

1

I → IQKD in AAB00795. Ref.3

Secondary structure

1

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549

Helix Strand Turn

Details...

Beta strand

20 – 25

6

Turn

37 – 39

3

Beta strand

60 – 65

6

Beta strand

71 – 77

7

Beta strand

79 – 82

4

Beta strand

87 – 92

6

Beta strand

99 – 103

5

Beta strand

109 – 112

4

Beta strand

117 – 120

4

Helix

123 – 125

3

Helix

126 – 135

10

Beta strand

156 – 166

11

Beta strand

168 – 174

7

Beta strand

196 – 200

5

Beta strand

202 – 205

4

Beta strand

211 – 217

7

Beta strand

225 – 230

6

Beta strand

233 – 236

4

Helix

241 – 243

3

Beta strand

248 – 253

6

Beta strand

266 – 274

9

Turn

275 – 278

4

Beta strand

284 – 289

6

Helix

306 – 315

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform p65 [UniParc]. Last modified October 1, 1993. Version 1. Checksum: BDF1673D2FE398B9	FASTA	549	60,212
	10 20 30 40 50 60 MDDLFPLIFP SEPAQASGPY VEIIEQPKQR GMRFRYKCEG RSAGSIPGER STDTTKTHPT 70 80 90 100 110 120 IKINGYTGPG TVRISLVTKD PPHRPHPHEL VGKDCRDGYY EADLCPDRSI HSFQNLGIQC 130 140 150 160 170 180 VKKRDLEQAI SQRIQTNNNP FHVPIEEQRG DYDLNAVRLC FQVTVRDPAG RPLLLTPVLS 190 200 210 220 230 240 HPIFDNRAPN TAELKICRVN RNSGSCLGGD EIFLLCDKVQ KEDIEVYFTG PGWEARGSFS 250 260 270 280 290 300 QADVHRQVAI VFRTPPYADP SLQAPVRVSM QLRRPSDREL SEPMEFQYLP DTDDRHRIEE 310 320 330 340 350 360 KRKRTYETFK SIMKKSPFNG PTEPRPPTRR IAVPTRNSTS VPKPAPQPYT FPASLSTINF 370 380 390 400 410 420 DEFSPMLLPS GQISNQALAL APSSAPVLAQ TMVPSSAMVP LAQPPAPAPV LTPGPPQSLS 430 440 450 460 470 480 APVPKSTQAG EGTLSEALLH LQFDADEDLG ALLGNSTDPG VFTDLASVDN SEFQQLLNQG 490 500 510 520 530 540 VSMSHSTAEP MLMEYPEAIT RLVTGSQRPP DPAPTPLGTS GLPNGLSGDE DFSSIADMDF SALLSQISS
	Isoform p65 delta. Checksum: F834FD0302D351BD	FASTA	539	59,061
	10 20 30 40 50 60 MDDLFPLIFP SEPAQASGPY VEIIEQPKQR GMRFRYKCEG RSAGSIPGER STDTTKTHPT 70 80 90 100 110 120 IKINGYTGPG TVRISLVTKD PPHRPHPHEL VGKDCRDGYY EADLCPDRSI HSFQNLGIQC 130 140 150 160 170 180 VKKRDLEQAI SQRIQTNNNP FHVPIEEQRG DYDLNAVRLC FQVTVRDPAG RPLLLTPVLS 190 200 210 220 230 240 HPIFDNRAPN TAELKICRVN RNSGSCLGGD EIFLLCDKVQ KGWEARGSFS QADVHRQVAI 250 260 270 280 290 300 VFRTPPYADP SLQAPVRVSM QLRRPSDREL SEPMEFQYLP DTDDRHRIEE KRKRTYETFK 310 320 330 340 350 360 SIMKKSPFNG PTEPRPPTRR IAVPTRNSTS VPKPAPQPYT FPASLSTINF DEFSPMLLPS 370 380 390 400 410 420 GQISNQALAL APSSAPVLAQ TMVPSSAMVP LAQPPAPAPV LTPGPPQSLS APVPKSTQAG 430 440 450 460 470 480 EGTLSEALLH LQFDADEDLG ALLGNSTDPG VFTDLASVDN SEFQQLLNQG VSMSHSTAEP 490 500 510 520 530 MLMEYPEAIT RLVTGSQRPP DPAPTPLGTS GLPNGLSGDE DFSSIADMDF SALLSQISS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide." Nolan G.P., Ghosh S., Liou H.C., Tempst P., Baltimore D. Cell 64:961-969(1991) [PubMed: 2001591] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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] (ISOFORM P65). Strain: C57BL/6J. Tissue: Mammary gland.
[3]	"Cloning of the murine relA (p65 NF-kappa B) gene and comparison to the human gene reveals a distinct first intron." Linker R.A., Baeuerle P.A., Kaltschmidt C. Gene 176:119-124(1996) [PubMed: 8918242] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. Strain: BALB/c.
[4]	"Genomic organization of the gene encoding the p65 subunit of NF-kappa B: multiple variants of the p65 protein may be generated by alternative splicing." Deloukas P., van Loon A.P.G.M. Hum. Mol. Genet. 2:1895-1900(1993) [PubMed: 8281153] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 188-252, ALTERNATIVE SPLICING. Strain: BALB/c.
[5]	"Role of unphosphorylated, newly synthesized IkappaB beta in persistent activation of NF-kappaB." Suyang H., Phillips R.J., Douglas I., Ghosh S. Mol. Cell. Biol. 16:5444-5449(1996) [PubMed: 8816457] [Abstract] Cited for: INTERACTION WITH NFKBIB.
[6]	"Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor." Fiorini E., Schmitz I., Marissen W.E., Osborn S.L., Touma M., Sasada T., Reche P.A., Tibaldi E.V., Hussey R.E., Kruisbeek A.M., Reinherz E.L., Clayton L.K. Mol. Cell 9:637-648(2002) [PubMed: 11931770] [Abstract] Cited for: INTERACTION WITH NFKBID.
[7]	"Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation." Duran A., Diaz-Meco M.T., Moscat J. EMBO J. 22:3910-3918(2003) [PubMed: 12881425] [Abstract] Cited for: PHOSPHORYLATION AT SER-311.
[8]	"Critical role of RelB serine 368 for dimerization and p100 stabilization." Maier H.J., Marienfeld R., Wirth T., Baumann B. J. Biol. Chem. 278:39242-39250(2003) [PubMed: 12874295] [Abstract] Cited for: MUTAGENESIS OF SER-281.
[9]	"A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells." Goriely S., Van Lint C., Dadkhah R., Libin M., De Wit D., Demonte D., Willems F., Goldman M. J. Exp. Med. 199:1011-1016(2004) [PubMed: 15051764] [Abstract] Cited for: IDENTIFICATION IN THE NF-KAPPA-B P65-P50 COMPLEX, IDENTIFICATION IN THE NF-KAPPA-B P65-P65 COMPLEX.
[10]	"Tumor necrosis factor alpha induction of NF-kappaB requires the novel coactivator SIMPL." Kwon H.-J., Breese E.H., Vig-Varga E., Luo Y., Lee Y., Goebl M.G., Harrington M.A. Mol. Cell. Biol. 24:9317-9326(2004) [PubMed: 15485901] [Abstract] Cited for: INTERACTION WITH IRAK1BP1.
[11]	"Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression." Covic M., Hassa P.O., Saccani S., Buerki C., Meier N.I., Lombardi C., Imhof R., Bedford M.T., Natoli G., Hottiger M.O. EMBO J. 24:85-96(2005) [PubMed: 15616592] [Abstract] Cited for: INTERACTION WITH CARM1.
[12]	"The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation." Huxford T., Huang D.B., Malek S., Ghosh G. Cell 95:759-770(1998) [PubMed: 9865694] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 19-291.
[13]	"A novel DNA recognition mode by the NF-kappa B p65 homodimer." Chen Y.Q., Ghosh S., Ghosh G. Nat. Struct. Biol. 5:67-73(1998) [PubMed: 9437432] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 19-291.
[14]	"Crystal structure of p50/p65 heterodimer of transcription factor NF-kappaB bound to DNA." Chen F.E., Huang D.B., Chen Y.Q., Ghosh G. Nature 391:410-413(1998) [PubMed: 9450761] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M61909 mRNA. Translation: AAA39811.1.
BC003818 mRNA. Translation: AAH03818.1.
L77155 Genomic DNA. Translation: AAB00795.1.
Z22952 Genomic DNA. Translation: CAA80528.1.

IPI

IPI00134188.
IPI00229014.

PIR

A37932.
PC4233.
S48113.

RefSeq

NP_033071.1.

UniGene

Mm.249966

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BFT	X-ray	2.00	A/B	191-291	[»]
1IKN	X-ray	2.30	A	19-304	[»]
1K3Z	X-ray	2.50	A/B	191-326	[»]
1LE5	X-ray	2.75	A/E	20-291	[»]
1LE9	X-ray	3.00	A/E	20-291	[»]
1LEI	X-ray	2.70	A	20-291	[»]
1MY5	X-ray	1.80	A/B	191-304	[»]
1MY7	X-ray	1.49	A/B	191-304	[»]
1OY3	X-ray	2.05	B/C	191-326	[»]
1RAM	X-ray	2.70	A/B	19-291	[»]
1VKX	X-ray	2.90	A	20-291	[»]
2I9T	X-ray	2.80	A	19-291	[»]
2RAM	X-ray	2.40	A/B	19-291	[»]

SMR

Q04207. Positions 20-319.

DisProt

DP00129.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6219N.

IntAct

Q04207. 14 interactions.

STRING

Q04207.

PTM databases

PhosphoSite

Q04207.

Proteomic databases

PRIDE

Q04207.

Genome annotation databases

Ensembl

ENSMUST00000025867; ENSMUSP00000025867; ENSMUSG00000024927; Mus musculus. [Genome view]

GeneID

19697.

KEGG

mmu:19697.

UCSC

uc008gee.1. mouse.

Organism-specific databases

CTD

19697.

MGI

MGI:103290. Rela.

Phylogenomic databases

HOGENOM

HBG268789.

HOVERGEN

Q04207.

InParanoid

Q04207.

OMA

KPAPQPY.

OrthoDB

EOG9SR0GB.

PhylomeDB

Q04207.

Gene expression databases

ArrayExpress

Q04207.

Bgee

Q04207.

Genevestigator

Q04207.

GermOnline

ENSMUSG00000024927. Mus musculus.

Family and domain databases

InterPro

IPR013783. Ig-like_fold.
IPR014756. Ig_E-set.
IPR002909. IPT_TIG_rcpt.
IPR000451. NF_Rel_dor.
IPR008967. p53-like_TF_DNA-bd.
IPR011539. RHD.
[Graphical view]

Gene3D

G3DSA:2.60.40.10. Ig-like_fold. 1 hit.
G3DSA:2.60.40.340. RHD. 1 hit.

Pfam

PF00554. RHD. 1 hit.
[Graphical view]

PRINTS

PR00057. NFKBTNSCPFCT.

SMART

SM00429. IPT. 1 hit.
[Graphical view]

PROSITE

PS01204. REL_1. 1 hit.
PS50254. REL_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

297048.

SOURCE

Search...

Entry information

Entry name

TF65_MOUSE

Accession

Primary (citable) accession number: Q04207
Secondary accession number(s): Q62025

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1993
Last sequence update:	October 1, 1993
Last modified:	January 19, 2010
This is version 112 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)