NF-kappa-B inhibitor alpha

Details

Name
NF-kappa-B inhibitor alpha
Synonyms
  • I-kappa-B-alpha
  • IkappaBalpha
  • IkB-alpha
  • IKBA
  • MAD3
  • Major histocompatibility complex enhancer-binding protein MAD3
  • NFKBI
Gene Name
NFKBIA
Organism
Humans
Amino acid sequence
>lcl|BSEQ0021363|NF-kappa-B inhibitor alpha
MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVP
RGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVI
TNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATN
YNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCG
ADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTE
DELPYDDCVFGGQRLTL
Number of residues
317
Molecular Weight
35608.65
Theoretical pI
4.31
GO Classification
Functions
enzyme binding / identical protein binding / NF-kappaB binding / nuclear localization sequence binding / transcription factor binding / ubiquitin protein ligase binding
Processes
apoptotic process / cellular response to cold / cytoplasmic sequestering of NF-kappaB / cytoplasmic sequestering of transcription factor / Fc-epsilon receptor signaling pathway / innate immune response / lipopolysaccharide-mediated signaling pathway / MyD88-dependent toll-like receptor signaling pathway / MyD88-independent toll-like receptor signaling pathway / negative regulation of apoptotic process / negative regulation of DNA binding / negative regulation of lipid storage / negative regulation of macrophage derived foam cell differentiation / negative regulation of myeloid cell differentiation / negative regulation of NF-kappaB transcription factor activity / negative regulation of Notch signaling pathway / neurotrophin TRK receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of cellular protein metabolic process / positive regulation of cholesterol efflux / positive regulation of NF-kappaB transcription factor activity / positive regulation of transcription from RNA polymerase II promoter / positive regulation of type I interferon production / protein import into nucleus, translocation / regulation of cell proliferation / regulation of NF-kappaB import into nucleus / response to exogenous dsRNA / response to muramyl dipeptide / response to muscle stretch / stimulatory C-type lectin receptor signaling pathway / T cell receptor signaling pathway / toll-like receptor 10 signaling pathway / toll-like receptor 2 signaling pathway / toll-like receptor 3 signaling pathway / toll-like receptor 4 signaling pathway / toll-like receptor 5 signaling pathway / toll-like receptor 9 signaling pathway / toll-like receptor signaling pathway / toll-like receptor TLR1 / toll-like receptor TLR6 / TRIF-dependent toll-like receptor signaling pathway / viral process
Components
cytoplasm / cytosol / I-kappaB/NF-kappaB complex / nucleus / plasma membrane
General Function
Ubiquitin protein ligase binding
Specific Function
Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0021364|NF-kappa-B inhibitor alpha (NFKBIA)
ATGTTCCAGGCGGCCGAGCGCCCCCAGGAGTGGGCCATGGAGGGCCCCCGCGACGGGCTG
AAGAAGGAGCGGCTACTGGACGACCGCCACGACAGCGGCCTGGACTCCATGAAAGACGAG
GAGTACGAGCAGATGGTCAAGGAGCTGCAGGAGATCCGCCTCGAGCCGCAGGAGGTGCCG
CGCGGCTCGGAGCCCTGGAAGCAGCAGCTCACCGAGGACGGGGACTCGTTCCTGCACTTG
GCCATCATCCATGAAGAAAAGGCACTGACCATGGAAGTGATCCGCCAGGTGAAGGGAGAC
CTGGCCTTCCTCAACTTCCAGAACAACCTGCAGCAGACTCCACTCCACTTGGCTGTGATC
ACCAACCAGCCAGAAATTGCTGAGGCACTTCTGGGAGCTGGCTGTGATCCTGAGCTCCGA
GACTTTCGAGGAAATACCCCCCTACACCTTGCCTGTGAGCAGGGCTGCCTGGCCAGCGTG
GGAGTCCTGACTCAGTCCTGCACCACCCCGCACCTCCACTCCATCCTGAAGGCTACCAAC
TACAATGGCCACACGTGTCTACACTTAGCCTCTATCCATGGCTACCTGGGCATCGTGGAG
CTTTTGGTGTCCTTGGGTGCTGATGTCAATGCTCAGGAGCCCTGTAATGGCCGGACTGCC
CTTCACCTCGCAGTGGACCTGCAAAATCCTGACCTGGTGTCACTCCTGTTGAAGTGTGGG
GCTGATGTCAACAGAGTTACCTACCAGGGCTATTCTCCCTACCAGCTCACCTGGGGCCGC
CCAAGCACCCGGATACAGCAGCAGCTGGGCCAGCTGACACTAGAAAACCTTCAGATGCTG
CCAGAGAGTGAGGATGAGGAGAGCTATGACACAGAGTCAGAGTTCACGGAGTTCACAGAG
GACGAGCTGCCCTATGATGACTGTGTGTTTGGAGGCCAGCGTCTGACGTTATGA
Chromosome Location
14
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP25963
UniProtKB Entry NameIKBA_HUMAN
GenBank Gene IDBC004983
GenAtlas IDNFKBIA
HGNC IDHGNC:7797
General References
  1. Haskill S, Beg AA, Tompkins SM, Morris JS, Yurochko AD, Sampson-Johannes A, Mondal K, Ralph P, Baldwin AS Jr: Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281-9. [PubMed:1829648]
  2. Jungnickel B, Staratschek-Jox A, Brauninger A, Spieker T, Wolf J, Diehl V, Hansmann ML, Rajewsky K, Kuppers R: Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med. 2000 Jan 17;191(2):395-402. [PubMed:10637284]
  3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039]
  4. Heilig R, Eckenberg R, Petit JL, Fonknechten N, Da Silva C, Cattolico L, Levy M, Barbe V, de Berardinis V, Ureta-Vidal A, Pelletier E, Vico V, Anthouard V, Rowen L, Madan A, Qin S, Sun H, Du H, Pepin K, Artiguenave F, Robert C, Cruaud C, Bruls T, Jaillon O, Friedlander L, Samson G, Brottier P, Cure S, Segurens B, Aniere F, Samain S, Crespeau H, Abbasi N, Aiach N, Boscus D, Dickhoff R, Dors M, Dubois I, Friedman C, Gouyvenoux M, James R, Madan A, Mairey-Estrada B, Mangenot S, Martins N, Menard M, Oztas S, Ratcliffe A, Shaffer T, Trask B, Vacherie B, Bellemere C, Belser C, Besnard-Gonnet M, Bartol-Mavel D, Boutard M, Briez-Silla S, Combette S, Dufosse-Laurent V, Ferron C, Lechaplais C, Louesse C, Muselet D, Magdelenat G, Pateau E, Petit E, Sirvain-Trukniewicz P, Trybou A, Vega-Czarny N, Bataille E, Bluet E, Bordelais I, Dubois M, Dumont C, Guerin T, Haffray S, Hammadi R, Muanga J, Pellouin V, Robert D, Wunderle E, Gauguet G, Roy A, Sainte-Marthe L, Verdier J, Verdier-Discala C, Hillier L, Fulton L, McPherson J, Matsuda F, Wilson R, Scarpelli C, Gyapay G, Wincker P, Saurin W, Quetier F, Waterston R, Hood L, Weissenbach J: The DNA sequence and analysis of human chromosome 14. Nature. 2003 Feb 6;421(6923):601-7. Epub 2003 Jan 1. [PubMed:12508121]
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  6. Ganchi PA, Sun SC, Greene WC, Ballard DW: I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 and requires the transactivation domain to inhibit NF-kappa B p65 DNA binding. Mol Biol Cell. 1992 Dec;3(12):1339-52. [PubMed:1493333]
  7. Scherer DC, Brockman JA, Chen Z, Maniatis T, Ballard DW: Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11259-63. [PubMed:7479976]
  8. Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C, Farahifar D, Rossi B, Auberger P, Baeuerle PA, Peyron JF: Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha. Cell. 1996 Sep 6;86(5):787-98. [PubMed:8797825]
  9. McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV: Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol Cell Biol. 1996 Mar;16(3):899-906. [PubMed:8622692]
  10. DiDonato J, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S, Karin M: Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol. 1996 Apr;16(4):1295-304. [PubMed:8657102]
  11. Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J: Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol Cell Biol. 1996 Apr;16(4):1401-9. [PubMed:8657113]
  12. Sachdev S, Hoffmann A, Hannink M: Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol Cell Biol. 1998 May;18(5):2524-34. [PubMed:9566872]
  13. Vuillard L, Nicholson J, Hay RT: A complex containing betaTrCP recruits Cdc34 to catalyse ubiquitination of IkappaBalpha. FEBS Lett. 1999 Jul 23;455(3):311-4. [PubMed:10437795]
  14. Gonen H, Bercovich B, Orian A, Carrano A, Takizawa C, Yamanaka K, Pagano M, Iwai K, Ciechanover A: Identification of the ubiquitin carrier proteins, E2s, involved in signal-induced conjugation and subsequent degradation of IkappaBalpha. J Biol Chem. 1999 May 21;274(21):14823-30. [PubMed:10329681]
  15. Weil R, Sirma H, Giannini C, Kremsdorf D, Bessia C, Dargemont C, Brechot C, Israel A: Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha. Mol Cell Biol. 1999 Sep;19(9):6345-54. [PubMed:10454581]
  16. Peters RT, Liao SM, Maniatis T: IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell. 2000 Mar;5(3):513-22. [PubMed:10882136]
  17. Tojima Y, Fujimoto A, Delhase M, Chen Y, Hatakeyama S, Nakayama K, Kaneko Y, Nimura Y, Motoyama N, Ikeda K, Karin M, Nakanishi M: NAK is an IkappaB kinase-activating kinase. Nature. 2000 Apr 13;404(6779):778-82. [PubMed:10783893]
  18. Fenwick C, Na SY, Voll RE, Zhong H, Im SY, Lee JW, Ghosh S: A subclass of Ras proteins that regulate the degradation of IkappaB. Science. 2000 Feb 4;287(5454):869-73. [PubMed:10657303]
  19. Huang TT, Kudo N, Yoshida M, Miyamoto S: A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes. Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1014-9. [PubMed:10655476]
  20. Rodriguez MS, Dargemont C, Hay RT: SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem. 2001 Apr 20;276(16):12654-9. Epub 2000 Dec 21. [PubMed:11124955]
  21. Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Lohmann SM, Walter U: Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex. J Biol Chem. 2010 Jun 11;285(24):18352-63. doi: 10.1074/jbc.M109.077602. Epub 2010 Mar 31. [PubMed:20356841]
  22. Ganesh L, Yoshimoto T, Moorthy NC, Akahata W, Boehm M, Nabel EG, Nabel GJ: Protein methyltransferase 2 inhibits NF-kappaB function and promotes apoptosis. Mol Cell Biol. 2006 May;26(10):3864-74. [PubMed:16648481]
  23. Cockman ME, Lancaster DE, Stolze IP, Hewitson KS, McDonough MA, Coleman ML, Coles CH, Yu X, Hay RT, Ley SC, Pugh CW, Oldham NJ, Masson N, Schofield CJ, Ratcliffe PJ: Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14767-72. Epub 2006 Sep 26. [PubMed:17003112]
  24. Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, Holsboer F, Arzt E: RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell. 2007 Oct 19;131(2):309-23. [PubMed:17956732]
  25. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, Gumucio DL, Shoham NG, Kastner DL: The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood. 2008 Sep 1;112(5):1794-803. doi: 10.1182/blood-2008-01-134932. Epub 2008 Jun 24. [PubMed:18577712]
  26. Wu K, Kovacev J, Pan ZQ: Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol Cell. 2010 Mar 26;37(6):784-96. doi: 10.1016/j.molcel.2010.02.025. [PubMed:20347421]
  27. Sun Z, Chen Z, Lawson SR, Fang Y: The cysteine protease domain of porcine reproductive and respiratory syndrome virus nonstructural protein 2 possesses deubiquitinating and interferon antagonism functions. J Virol. 2010 Aug;84(15):7832-46. doi: 10.1128/JVI.00217-10. Epub 2010 May 26. [PubMed:20504922]
  28. Gerez J, Fuertes M, Tedesco L, Silberstein S, Sevlever G, Paez-Pereda M, Holsboer F, Turjanski AG, Arzt E: In silico structural and functional characterization of the RSUME splice variants. PLoS One. 2013;8(2):e57795. doi: 10.1371/journal.pone.0057795. Epub 2013 Feb 28. [PubMed:23469069]
  29. Jacobs MD, Harrison SC: Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998 Dec 11;95(6):749-58. [PubMed:9865693]
  30. Huxford T, Huang DB, Malek S, Ghosh G: The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell. 1998 Dec 11;95(6):759-70. [PubMed:9865694]
  31. Courtois G, Smahi A, Reichenbach J, Doffinger R, Cancrini C, Bonnet M, Puel A, Chable-Bessia C, Yamaoka S, Feinberg J, Dupuis-Girod S, Bodemer C, Livadiotti S, Novelli F, Rossi P, Fischer A, Israel A, Munnich A, Le Deist F, Casanova JL: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest. 2003 Oct;112(7):1108-15. [PubMed:14523047]
  32. Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, Quinones R, Gelfand EW, Jain A: A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat. 2008 Jun;29(6):861-8. doi: 10.1002/humu.20740. [PubMed:18412279]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB05983Bardoxolone methylinvestigationalunknownDetails
DB06543AstaxanthininvestigationalunknownDetails
DB00945Acetylsalicylic acidapproved, vet_approvedunknowninhibitorDetails