UniProt Accession

 TF65_HUMAN; Q04206; Q6GTV1; Q6SLK1 

Genbank Protein ID

 M62399; Z22948; Z22949; Z22953; Z22950; Z22951; L19067; BC033522; AY455868 

Genbank Nucleotide ID

 AAA36408.1; CAA80524.2; CAA80524.2; CAA80524.2; CAA80524.2; CAA80524.2; AAA20946.1; AAH33522.1; AAR13863.1 

Protein Name

 Transcription factor p65 

Protein Synonyms/Alias

 Nuclear factor NF-kappa-B p65 subunit; Nuclear factor of kappa light polypeptide gene enhancer in B-cells 3 

Gene Name

 RELA 

Gene Synonyms/Alias

 NFKB3 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
37	RGMRFRYKCEGRSAG	methylation	[1]
122	NLGIQCVKKRDLEQA	acetylation	[2]
123	LGIQCVKKRDLEQAI	acetylation	[2]
195	APNTAELKICRVNRN	ubiquitination	[3]
218	EIFLLCDKVQKEDIE	acetylation	[4]
218	EIFLLCDKVQKEDIE	methylation	[5]
221	LLCDKVQKEDIEVYF	acetylation	[4]
221	LLCDKVQKEDIEVYF	methylation	[5]
310	KRTYETFKSIMKKSP	acetylation	[6, 7, 8]
310	KRTYETFKSIMKKSP	methylation	[9]
310	KRTYETFKSIMKKSP	ubiquitination	[3]
314	ETFKSIMKKSPFSGP	acetylation	[10]
314	ETFKSIMKKSPFSGP	methylation	[11]
315	TFKSIMKKSPFSGPT	acetylation	[10]
315	TFKSIMKKSPFSGPT	methylation	[11]

Reference

 [1] Regulation of NF-kappaB activity through lysine monomethylation of p65.
 Ea CK, Baltimore D.
 Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):18972-7. [PMID: 19864627]
 [2] Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65.
 Kiernan R, Brès V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M.
 J Biol Chem. 2003 Jan 24;278(4):2758-66. [PMID: 12419806]
 [3] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [4] Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB.
 Chen LF, Mu Y, Greene WC.
 EMBO J. 2002 Dec 2;21(23):6539-48. [PMID: 12456660]
 [5] Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65.
 Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, Gudkov AV, Stark GR.
 Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):46-51. [PMID: 20080798]
 [6] IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300.
 Hoberg JE, Popko AE, Ramsey CS, Mayo MW.
 Mol Cell Biol. 2006 Jan;26(2):457-71. [PMID: 16382138]
 [7] MAPK p38 regulates transcriptional activity of NF-kappaB in primary human astrocytes via acetylation of p65.
 Saha RN, Jana M, Pahan K.
 J Immunol. 2007 Nov 15;179(10):7101-9. [PMID: 17982102]
 [8] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [9] Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling.
 Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O.
 Nat Immunol. 2011 Jan;12(1):29-36. [PMID: 21131967]
 [10] Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65.
 Buerki C, Rothgiesser KM, Valovka T, Owen HR, Rehrauer H, Fey M, Lane WS, Hottiger MO.
 Nucleic Acids Res. 2008 Mar;36(5):1665-80. [PMID: 18263619]
 [11] Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit.
 Yang XD, Huang B, Li M, Lamb A, Kelleher NL, Chen LF.
 EMBO J. 2009 Apr 22;28(8):1055-66. [PMID: 19262565] 

Functional Description

 NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes 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. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. 

Sequence Annotation

 DOMAIN 19 306 RHD.
 REGION 415 459 Activation domain.
 MOTIF 301 304 Nuclear localization signal (Potential).
 MOTIF 536 544 9aaTAD.
 MOD_RES 38 38 Cysteine persulfide; alternate (By
 MOD_RES 38 38 S-nitrosocysteine; alternate (By
 MOD_RES 122 122 N6-acetyllysine; by PCAF and EP300;
 MOD_RES 123 123 N6-acetyllysine; by PCAF and EP300;
 MOD_RES 254 254 Phosphothreonine.
 MOD_RES 276 276 Phosphoserine; by RPS6KA4 and RPS6KA5.
 MOD_RES 281 281 Phosphoserine (Probable).
 MOD_RES 310 310 N6-acetyllysine; alternate.
 MOD_RES 310 310 N6-methyllysine; by SETD6; alternate (By
 MOD_RES 311 311 Phosphoserine; by PKC/PRKCZ (By
 MOD_RES 435 435 Phosphothreonine.
 MOD_RES 468 468 Phosphoserine; by IKKB and IKKE.
 MOD_RES 505 505 Phosphothreonine; by CHEK1.
 MOD_RES 529 529 Phosphoserine; by CK2.
 MOD_RES 536 536 Phosphoserine; by IKKB.
 CROSSLNK 37 37 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 122 122 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 123 123 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Acetylation; Activator; Alternative splicing; Complete proteome; Cytoplasm; DNA-binding; Host-virus interaction; Isopeptide bond; Methylation; Nucleus; Phosphoprotein; Reference proteome; S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 551 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005667; C:transcription factor complex; IDA:UniProtKB.
 GO:0003682; F:chromatin binding; IDA:UniProtKB.
 GO:0042802; F:identical protein binding; IDA:UniProtKB.
 GO:0042301; F:phosphate ion binding; IDA:UniProtKB.
 GO:0003705; F:RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
 GO:0043565; F:sequence-specific DNA binding; IEA:Compara.
 GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
 GO:0006117; P:acetaldehyde metabolic process; IEA:Compara.
 GO:0007568; P:aging; IEA:Compara.
 GO:0006968; P:cellular defense response; NAS:UniProtKB.
 GO:0071347; P:cellular response to interleukin-1; IDA:UniProtKB.
 GO:0071222; P:cellular response to lipopolysaccharide; IEA:Compara.
 GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
 GO:0019221; P:cytokine-mediated signaling pathway; IDA:UniProtKB.
 GO:0051607; P:defense response to virus; NAS:UniProtKB.
 GO:0001942; P:hair follicle development; IEA:Compara.
 GO:0006954; P:inflammatory response; IDA:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0001889; P:liver development; IEA:Compara.
 GO:0031293; P:membrane protein intracellular domain proteolysis; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
 GO:0046627; P:negative regulation of insulin receptor signaling pathway; IEA:Compara.
 GO:0042177; P:negative regulation of protein catabolic process; IEA:Compara.
 GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:MGI.
 GO:0009887; P:organ morphogenesis; IEA:Compara.
 GO:0008284; P:positive regulation of cell proliferation; IEA:Compara.
 GO:0032332; P:positive regulation of chondrocyte differentiation; IEA:Compara.
 GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
 GO:0045084; P:positive regulation of interleukin-12 biosynthetic process; IEA:Compara.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:MGI.
 GO:0014040; P:positive regulation of Schwann cell differentiation; IEA:Compara.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
 GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
 GO:0043200; P:response to amino acid stimulus; IEA:Compara.
 GO:0051591; P:response to cAMP; IEA:Compara.
 GO:0033590; P:response to cobalamin; IEA:Compara.
 GO:0042493; P:response to drug; IEA:Compara.
 GO:0042542; P:response to hydrogen peroxide; IEA:Compara.
 GO:0032868; P:response to insulin stimulus; IEA:Compara.
 GO:0009612; P:response to mechanical stimulus; IEA:Compara.
 GO:0043278; P:response to morphine; IEA:Compara.
 GO:0032495; P:response to muramyl dipeptide; IEA:Compara.
 GO:0032570; P:response to progesterone stimulus; IEA:Compara.
 GO:0010224; P:response to UV-B; IDA:UniProtKB.
 GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW. 

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. 

Pfam

 PF00554; RHD 

SMART

 SM00429; IPT 

PROSITE

 PS01204; REL_1
 PS50254; REL_2 

PRINTS

 PR00057; NFKBTNSCPFCT.