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NF-kappa B inhibitor alpha; IKB-alpha; MHC enhancer-binding protein MAD3; NF-kappa-B inhibitor alpha; I-kappa-B-alpha; IkappaBalpha; IkB-alpha; NFKBIA; IKBA (MAD3, NFKBI)

Function: - IKB-alpha specifically binds to NF-kappa B p65 inhibiting transcriptional activity of NF-kappa B by retaining it in the cytoplasm - binding to NF-kappa B is inhibited by H2O2, TNF, LPS, IL-1 & dsRNA, with all such in vitro inhibitions reversed by thiols - various stimuli, typically those associated with stress or pathogens, rapidly inactivate IKB-alpha, liberating NF-kappa B to translocate to the nucleus & initiate transcription of genes important for the defense of the organism [2] - activation of NF-kappa B correlates with phosphorylation of IKB-alpha on Ser-32 & Ser-36 which is required for ubiquitination & subsequent proteolysis of IKB-alpha - phosphorylation of IKB-alpha does not itself dissociate complexes of NF-kappa B/IKB-alpha [2] - inhibits 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 & proinflammatory responses, becomes phosphorylated promoting ubiquitination & degradation, enabling the dimeric RELA to translocate to the nucleus & activate transcription - interacts with RELA; the interaction requires the nuclear import signal - interacts with NKIRAS1 & NKIRAS2 - part of a 70-90 kD complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, IKBKAP & MAP3K14 - interacts with HBV protein X - interacts with RWDD3; interaction enhances sumoylation - phosphorylated; disables inhibition of NF-kappa-B DNA-binding activity - ubiquitinated; subsequent to stimulus-dependent Ser phosphorylation - sumoylated; sumoylation requires the presence of the nuclear import signal Structure: - belongs to the NF-kappa-B inhibitor family - contains 5 ANK repeats Compartment: - cytoplasm. nucleus - shuttles between the nucleus & the cytoplasm by a nuclear localization signal (NLS) & a CRM1-dependent nuclear export (putative) Expression: induced in adherent monocytes Pathology: - defects in NFKBIA are a cause of autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency

General

DNA-binding protein IKB protein transcription factor (TF)

Properties

SIZE: entity length = 317 aa MW = 36 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: Ser phosphorylation site {S32} Ser phosphorylation site {S36} Tyr phosphorylation site {Y42} nuclear export signal {45-54} ankyrin repeat NAME: ankyrin repeat SITE: 73-103 ankyrin repeat NAME: ankyrin repeat SITE: 110-139 MOTIF: nuclear import signal {110-120} ankyrin repeat NAME: ankyrin repeat SITE: 143-172 ankyrin repeat NAME: ankyrin repeat SITE: 182-211 ankyrin repeat NAME: ankyrin repeat SITE: 216-245 Ser phosphorylation site {S283} Ser phosphorylation site {S288} Thr phosphorylation site {T291} Ser phosphorylation site {S293} Thr phosphorylation site {T299}

Database Correlations

OMIM 164008 MORBIDMAP 164008 UniProt P25963 Pfam PF00023 Kegg hsa:4792

References

  1. Ruben SM, Dillon PJ, Schreck R, Henkel T, Chen CH, Maher M, Baeuerle PA, Rosen CA. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science. 1991 Oct 4;254(5028):11. PMID: 1925549 - Ruben SM, Dillon PJ, Schreck R, Henkel T, Chen CH, Maher M, Baeuerle PA, Rosen CA. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science. 1991 Mar 22;251(5000):1490-3. Erratum in: Science. 1991 Oct 4;254(5028):11. PMID: 2006423
  2. Nigg EA, Baeuerle PA, Luhrmann R. Nuclear import-export: in search of signals and mechanisms. Cell. 1991 Jul 12;66(1):15-22. Review. No abstract available. PMID: 1712670
  3. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485-8. PMID: 7878466
  4. UniProt :accession P25963
  5. NFKBIAbase; Note: NFKBIA mutation db http://bioinf.uta.fi/NFKBIAbase/
  6. SeattleSNPs http://pga.gs.washington.edu/data/nfkbia/

Component-of

molecular complex