Reviewed, UniProtKB/Swiss-Prot Q04206 (TF65_HUMAN)

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

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	551 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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. 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 By similarity.Interacts with NFKBID By similarity. Interacts with NFKBIA. Interacts with GSK3B. Interacts with NFKBIB By similarity. Interacts with NFKBIE. Interacts with NFKBIZ By similarity. 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 UXT.
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. Phosphorylation on 'Ser-536' stimulates acetylation on 'Lys-310' and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. 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.
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	anti-apoptosis Inferred from direct assay. Source: UniProtKB cellular defense response Non-traceable author statement. Source: UniProtKB cytokine and chemokine mediated signaling pathway Inferred from direct assay. Source: UniProtKB defense response to virus Non-traceable author statement. Source: UniProtKB inflammatory response Inferred from direct assay. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Inferred from direct assay. Source: MGI regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: InterPro response to UV-B Inferred from direct assay. Source: UniProtKB response to organic substance Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Inferred from Experiment. Source: Reactome transcription factor complex Inferred from direct assay. Source: UniProtKB
Molecular function	NF-kappaB binding Inferred from physical interaction. Source: UniProtKB RNA polymerase II transcription factor activity, enhancer binding Inferred from direct assay. Source: UniProtKB identical protein binding Ref.14 Inferred from direct assay. Source: UniProtKB phosphate binding Ref.13 Inferred from direct assay. Source: UniProtKB protein N-terminus binding Inferred from physical interaction. Source: UniProtKB protein kinase binding Ref.13 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-73886,EBI-73886
AATF	Q9NY61	2	EBI-73886,EBI-372428
ATF3	P18847	1	EBI-73886,EBI-712767
CDK5RAP3	Q96JB5	3	EBI-73886,EBI-718818
CHUK	O15111	1	EBI-73886,EBI-81249
COMMD1	Q8N668	2	EBI-73886,EBI-1550112
CREBBP	Q92793	1	EBI-73886,EBI-81215
DHX9	Q08211	3	EBI-73886,EBI-352022
HDAC1	Q13547	2	EBI-73886,EBI-301834
MTDH	Q86UE4	1	EBI-73886,EBI-1046588
NFKB1	P19838	2	EBI-73886,EBI-300010
NFKBIA	P25963	3	EBI-73886,EBI-307386
NFKBIB	Q15653	3	EBI-73886,EBI-352889
PDCD11	Q14690	1	EBI-73886,EBI-300028
REL	Q04864	2	EBI-73886,EBI-307352
RPS3	P23396	5	EBI-73886,EBI-351193
RPS6KA5	O75582	1	EBI-73886,EBI-73869
TGM2	P21980	2	EBI-73886,EBI-727668
TP53BP2	Q13625-2	5	EBI-73886,EBI-287091
UXT	Q9UBK9	3	EBI-73886,EBI-357355

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q04206-1)

Also known as: p65;

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: Q04206-2)

Also known as: p65 delta 2;

The sequence of this isoform differs from the canonical sequence as follows:
     13-25: Missing.
     506-506: Missing.

Isoform 3 (identifier: Q04206-3)

Also known as: p65 delta;

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

Isoform 4 (identifier: Q04206-4)

The sequence of this isoform differs from the canonical sequence as follows:
     143-145: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 551

551

Transcription factor p65

PRO_0000205169

Regions

Domain

19 – 306

288

RHD

Region

415 – 459

45

Activation domain

Motif

301 – 304

4

Nuclear localization signal Potential

Amino acid modifications

Modified residue

122

1

N6-acetyllysine; by PCAF and EP300

Modified residue

123

1

N6-acetyllysine; by PCAF and EP300

Modified residue

254

1

Phosphothreonine

Modified residue

276

1

Phosphoserine; by RPS6KA4 and RPS6KA5

Modified residue

281

1

Phosphoserine Probable

Modified residue

310

1

N6-acetyllysine

Modified residue

311

1

Phosphoserine; by PKC/PRKCZ By similarity

Modified residue

435

1

Phosphothreonine

Modified residue

468

1

Phosphoserine; by IKKB and IKKE

Modified residue

505

1

Phosphothreonine; by CHK1

Modified residue

529

1

Phosphoserine; by CK2

Modified residue

536

1

Phosphoserine; by IKKB

Natural variations

Alternative sequence

13 – 25

13

Missing in isoform 2.

VSP_005587

Alternative sequence

143 – 145

3

Missing in isoform 4.

VSP_031245

Alternative sequence

222 – 231

10

Missing in isoform 3.

VSP_012031

Alternative sequence

506

1

Missing in isoform 2.

VSP_005588

Experimental info

Mutagenesis

254

1

T → A: Abolishes interaction with PIN1

Mutagenesis

276

1

S → C: Loss of phosphorylation

Sequence conflict

49

1

E → R in CAA80524. Ref.2

Sequence conflict

180

1

S → P in AAA36408. Ref.1

Sequence conflict

372 – 380

9

QISQASALA → RSARPRLG in CAA80524. Ref.2

Secondary structure

1

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551

Helix Strand Turn

Details...

Beta strand

21 – 25

5

Beta strand

30 – 32

3

Beta strand

39 – 41

3

Beta strand

53 – 55

3

Beta strand

60 – 63

4

Beta strand

68 – 80

13

Beta strand

87 – 92

6

Beta strand

97 – 104

8

Beta strand

117 – 119

3

Helix

126 – 129

4

Turn

130 – 137

8

Beta strand

156 – 166

11

Beta strand

168 – 173

6

Beta strand

183 – 188

6

Beta strand

196 – 200

5

Beta strand

202 – 205

4

Beta strand

211 – 217

7

Beta strand

225 – 230

6

Beta strand

233 – 238

6

Helix

241 – 243

3

Turn

246 – 248

3

Beta strand

249 – 253

5

Beta strand

266 – 273

8

Turn

275 – 277

3

Beta strand

284 – 289

6

Helix

294 – 302

9

Helix

306 – 312

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (p65) [UniParc]. Last modified April 26, 2005. Version 2. Checksum: 8147A6AF9F2445C6	FASTA	551	60,219
	10 20 30 40 50 60 MDELFPLIFP AEPAQASGPY VEIIEQPKQR GMRFRYKCEG RSAGSIPGER STDTTKTHPT 70 80 90 100 110 120 IKINGYTGPG TVRISLVTKD PPHRPHPHEL VGKDCRDGFY EAELCPDRCI HSFQNLGIQC 130 140 150 160 170 180 VKKRDLEQAI SQRIQTNNNP FQVPIEEQRG DYDLNAVRLC FQVTVRDPSG RPLRLPPVLS 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 SIMKKSPFSG PTDPRPPPRR IAVPSRSSAS VPKPAPQPYP FTSSLSTINY 370 380 390 400 410 420 DEFPTMVFPS GQISQASALA PAPPQVLPQA PAPAPAPAMV SALAQAPAPV PVLAPGPPQA 430 440 450 460 470 480 VAPPAPKPTQ AGEGTLSEAL LQLQFDDEDL GALLGNSTDP AVFTDLASVD NSEFQQLLNQ 490 500 510 520 530 540 GIPVAPHTTE PMLMEYPEAI TRLVTGAQRP PDPAPAPLGA PGLPNGLLSG DEDFSSIADM 550 DFSALLSQIS S
	Isoform 2 (p65 delta 2) [UniParc]. Checksum: A1F26DF2F53E662E		537	58,807
	10 20 30 40 50 60 MDELFPLIFP AEQPKQRGMR FRYKCEGRSA GSIPGERSTD TTKTHPTIKI NGYTGPGTVR 70 80 90 100 110 120 ISLVTKDPPH RPHPHELVGK DCRDGFYEAE LCPDRCIHSF QNLGIQCVKK RDLEQAISQR 130 140 150 160 170 180 IQTNNNPFQV PIEEQRGDYD LNAVRLCFQV TVRDPSGRPL RLPPVLSHPI FDNRAPNTAE 190 200 210 220 230 240 LKICRVNRNS GSCLGGDEIF LLCDKVQKED IEVYFTGPGW EARGSFSQAD VHRQVAIVFR 250 260 270 280 290 300 TPPYADPSLQ APVRVSMQLR RPSDRELSEP MEFQYLPDTD DRHRIEEKRK RTYETFKSIM 310 320 330 340 350 360 KKSPFSGPTD PRPPPRRIAV PSRSSASVPK PAPQPYPFTS SLSTINYDEF PTMVFPSGQI 370 380 390 400 410 420 SQASALAPAP PQVLPQAPAP APAPAMVSAL AQAPAPVPVL APGPPQAVAP PAPKPTQAGE 430 440 450 460 470 480 GTLSEALLQL QFDDEDLGAL LGNSTDPAVF TDLASVDNSE FQQLLNQGIP VAPHTTEPML 490 500 510 520 530 MEYPEAITRL VTAQRPPDPA PAPLGAPGLP NGLLSGDEDF SSIADMDFSA LLSQISS
	Isoform 3 (p65 delta) [UniParc]. Checksum: 49F0493E19798AD1		541	59,068
	10 20 30 40 50 60 MDELFPLIFP AEPAQASGPY VEIIEQPKQR GMRFRYKCEG RSAGSIPGER STDTTKTHPT 70 80 90 100 110 120 IKINGYTGPG TVRISLVTKD PPHRPHPHEL VGKDCRDGFY EAELCPDRCI HSFQNLGIQC 130 140 150 160 170 180 VKKRDLEQAI SQRIQTNNNP FQVPIEEQRG DYDLNAVRLC FQVTVRDPSG RPLRLPPVLS 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 SIMKKSPFSG PTDPRPPPRR IAVPSRSSAS VPKPAPQPYP FTSSLSTINY DEFPTMVFPS 370 380 390 400 410 420 GQISQASALA PAPPQVLPQA PAPAPAPAMV SALAQAPAPV PVLAPGPPQA VAPPAPKPTQ 430 440 450 460 470 480 AGEGTLSEAL LQLQFDDEDL GALLGNSTDP AVFTDLASVD NSEFQQLLNQ GIPVAPHTTE 490 500 510 520 530 540 PMLMEYPEAI TRLVTGAQRP PDPAPAPLGA PGLPNGLLSG DEDFSSIADM DFSALLSQIS S
	Isoform 4 [UniParc]. Checksum: ED40EF8B91F0A19A		548	59,910
	10 20 30 40 50 60 MDELFPLIFP AEPAQASGPY VEIIEQPKQR GMRFRYKCEG RSAGSIPGER STDTTKTHPT 70 80 90 100 110 120 IKINGYTGPG TVRISLVTKD PPHRPHPHEL VGKDCRDGFY EAELCPDRCI HSFQNLGIQC 130 140 150 160 170 180 VKKRDLEQAI SQRIQTNNNP FQEEQRGDYD LNAVRLCFQV TVRDPSGRPL RLPPVLSHPI 190 200 210 220 230 240 FDNRAPNTAE LKICRVNRNS GSCLGGDEIF LLCDKVQKED IEVYFTGPGW EARGSFSQAD 250 260 270 280 290 300 VHRQVAIVFR TPPYADPSLQ APVRVSMQLR RPSDRELSEP MEFQYLPDTD DRHRIEEKRK 310 320 330 340 350 360 RTYETFKSIM KKSPFSGPTD PRPPPRRIAV PSRSSASVPK PAPQPYPFTS SLSTINYDEF 370 380 390 400 410 420 PTMVFPSGQI SQASALAPAP PQVLPQAPAP APAPAMVSAL AQAPAPVPVL APGPPQAVAP 430 440 450 460 470 480 PAPKPTQAGE GTLSEALLQL QFDDEDLGAL LGNSTDPAVF TDLASVDNSE FQQLLNQGIP 490 500 510 520 530 540 VAPHTTEPML MEYPEAITRL VTGAQRPPDP APAPLGAPGL PNGLLSGDED FSSIADMDFS ALLSQISS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B." Ruben S.M., Dillon P.J., Schreck R., Henkel T., Chen C.-H., Maher M., Baeuerle P.A., Rosen C.A. Science 251:1490-1493(1991) [PubMed: 2006423] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"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], ALTERNATIVE SPLICING.
[3]	"An alternatively spliced transcript, p65 delta 2, of the gene encoding the p65 subunit of the transcription factor NF-kappa B." Lyle R., Valleley E.M., Sharpe P.T., Hewitt J.E. Gene 138:265-266(1994) [PubMed: 7907305] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Bone.
[4]	"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 4). Tissue: Colon.
[5]	SeattleSNPs program for genomic applications Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 4-551.
[6]	"Functional characterization of the NF-kappa B p65 transcriptional activator and an alternatively spliced derivative." Ruben S.M., Narayanan R., Klement J.F., Chen C.-H., Rosen C.A. Mol. Cell. Biol. 12:444-454(1992) [PubMed: 1732726] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 214-239 (ISOFORMS 1/2 AND 3), ACTIVATION DOMAIN.
[7]	"A novel complex between the p65 subunit of NF-kappa B and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene." Hansen S.K., Nerlov C., Zabel U., Verde P., Johnsen M., Baeuerle P.A., Blasi F. EMBO J. 11:205-213(1992) [PubMed: 1740106] [Abstract] Cited for: IDENTIFICAT