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35  structures 121  species 0  interactions 331  sequences 14  architectures

Family: IKBKB_SDD (PF18397)

Summary: IQBAL scaffold dimerization domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "IKK2". More...

IKK2 Edit Wikipedia article

IKBKB
Protein IKBKB PDB 3BRT.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIKBKB, IKK-beta, IKK2, IKKB, IMD15, NFKBIKB, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta, inhibitor of nuclear factor kappa B kinase subunit beta, IMD15A, IMD15B
External IDsOMIM: 603258 MGI: 1338071 HomoloGene: 7782 GeneCards: IKBKB
Gene location (Human)
Chromosome 8 (human)
Chr.Chromosome 8 (human)[1]
Chromosome 8 (human)
Genomic location for IKBKB
Genomic location for IKBKB
Band8p11.21Start42,271,302 bp[1]
End42,332,653 bp[1]
RNA expression pattern
PBB GE IKBKB 209342 s at fs.png

PBB GE IKBKB 209341 s at fs.png

PBB GE IKBKB 211027 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001190720
NM_001190721
NM_001190722
NM_001242778
NM_001556

NM_001159774
NM_010546

RefSeq (protein)

NP_001177649
NP_001229707
NP_001547

NP_001153246
NP_034676

Location (UCSC)Chr 8: 42.27 – 42.33 MbChr 8: 22.66 – 22.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene.

Function

IKK-β is an enzyme that serves as a protein subunit of IκB kinase, which is a component of the cytokine-activated intracellular signaling pathway involved in triggering immune responses. IKK's activity causes activation of a transcription factor known as Nuclear Transcription factor kappa-B or NF-κB. Activated IKK-β phosphorylates a protein called the inhibitor of NF-κB, IκB (IκBα), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the ubiquitination pathway, freeing NF-κB, and allowing its entry into the nucleus of the cell where it activates various genes involved in inflammation and other immune responses.

Clinical significance

IKK-β plays a significant role in brain cells following a stroke.[citation needed] If NF-κB activation by IKK-β is blocked, damaged cells within the brain stay alive, and according to a study performed by the University of Heidelberg and the University of Ulm, the cells even appear to make some recovery.[5]

Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[6][6] The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[7]

Model organisms

Model organisms have been used in the study of IKK-β function. The size of an infarct, or tissue killed or damaged by ischemia, is reduced in mice in which IKK-β has been blocked.[8] Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event.[5] Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours.[9] In another study, researchers found that inhibiting IKK-β prevented kidney and wasting diseases in an animal model used to study wasting diseases of human AIDS sufferers.[10]

A conditional knockout mouse line, called Ikbkbtm1a(EUCOMM)Wtsi[15][16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[17][18][19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][20] Twenty six tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals.[13]

Interactions

IKK-β (IKBKB) has been shown to interact with

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104365 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031537 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b BBC News. 14 November 2005. Stroke 'cell-death trigger' found. Retrieved on June 28, 2007.
  6. ^ a b Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
  7. ^ "SAR113945 published clinical trials".
  8. ^ Schwaninger M, Inta I, Herrmann O (2006). "NF-kappaB signalling in cerebral ischaemia". Biochemical Society Transactions. 34 (Pt 6): 1291–4. doi:10.1042/BST0341291. PMID 17073804.
  9. ^ Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Köhrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T, Pasparakis M, Schwaninger M (2005). "IKK mediates ischemia-induced neuronal death". Nature Medicine. 11 (12): 1322–9. doi:10.1038/nm1323. PMID 16286924.
  10. ^ Heckmann A, Waltzinger C, Jolicoeur P, Dreano M, Kosco-Vilbois MH, Sagot Y (2004). "IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS". Am. J. Pathol. 164 (4): 1253–62. doi:10.1016/S0002-9440(10)63213-0. PMC 1615343. PMID 15039214.
  11. ^ "Salmonella infection data for Ikbkb". Wellcome Trust Sanger Institute.
  12. ^ "Citrobacter infection data for Ikbkb". Wellcome Trust Sanger Institute.
  13. ^ a b c Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248): 0. doi:10.1111/j.1755-3768.2010.4142.x.
  14. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  15. ^ "International Knockout Mouse Consortium".
  16. ^ "Mouse Genome Informatics".
  17. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  18. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  19. ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  20. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
  21. ^ a b c Chen G, Cao P, Goeddel DV (February 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell. 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. ISSN 1097-2765. PMID 11864612.
  22. ^ Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (October 1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell. 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. ISSN 0092-8674. PMID 9346241.
  23. ^ a b Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome". J. Cell. Biochem. 86 (4): 613–23. doi:10.1002/jcb.10270. ISSN 0730-2312. PMID 12210728.
  24. ^ May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex". Science. 289 (5484): 1550–4. doi:10.1126/science.289.5484.1550. ISSN 0036-8075. PMID 10968790.
  25. ^ a b c d Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (October 1997). "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science. 278 (5339): 866–9. doi:10.1126/science.278.5339.866. ISSN 0036-8075. PMID 9346485.
  26. ^ a b Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (October 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell. 103 (2): 351–61. doi:10.1016/S0092-8674(00)00126-4. ISSN 0092-8674. PMID 11057907.
  27. ^ Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM (November 2001). "Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation". Mol. Cell. Biol. 21 (21): 7207–17. doi:10.1128/MCB.21.21.7207-7217.2001. ISSN 0270-7306. PMC 99896. PMID 11585904.
  28. ^ Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, Gaynor RB (November 2001). "Regulation of beta-catenin function by the IkappaB kinases". J. Biol. Chem. 276 (45): 42276–86. doi:10.1074/jbc.M104227200. ISSN 0021-9258. PMID 11527961.
  29. ^ Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U (October 2002). "Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases". J. Biol. Chem. 277 (40): 37029–36. doi:10.1074/jbc.M205069200. ISSN 0021-9258. PMID 12133833.
  30. ^ a b Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase". Mol. Cell. Biol. 22 (10): 3549–61. doi:10.1128/MCB.22.10.3549-3561.2002. ISSN 0270-7306. PMC 133790. PMID 11971985.
  31. ^ Shifera AS, Horwitz MS (March 2008). "Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes". Mol. Immunol. 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. ISSN 0161-5890. PMID 18207244.
  32. ^ Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. ISSN 0021-9258. PMID 11096118.
  33. ^ Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
  34. ^ Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM (February 1999). "IκB Kinase (IKK)-Associated Protein 1, a Common Component of the Heterogeneous IKK Complex". Mol. Cell. Biol. 19 (2): 1526–38. doi:10.1128/mcb.19.2.1526. ISSN 0270-7306. PMC 116081. PMID 9891086.
  35. ^ Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. doi:10.1038/26254. ISSN 0028-0836. PMID 9751059.
  36. ^ Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (May 2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. ISSN 0021-9258. PMID 11278268.
  37. ^ Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C (February 2001). "Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα". Mol. Cell. Biol. 21 (4): 1024–35. doi:10.1128/MCB.21.4.1024-1035.2001. ISSN 0270-7306. PMC 99557. PMID 11158290.
  38. ^ Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C (September 1999). "NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes". EMBO J. 18 (17): 4766–78. doi:10.1093/emboj/18.17.4766. ISSN 0261-4189. PMC 1171549. PMID 10469655.
  39. ^ Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB (January 2004). "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". J. Biol. Chem. 279 (3): 1739–46. doi:10.1074/jbc.M306273200. ISSN 0021-9258. PMID 14585847.
  40. ^ Zhang SQ, Kovalenko A, Cantarella G, Wallach D (March 2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity. 12 (3): 301–11. doi:10.1016/S1074-7613(00)80183-1. ISSN 1074-7613. PMID 10755617.
  41. ^ Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (September 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene. 19 (39): 4451–60. doi:10.1038/sj.onc.1203812. ISSN 0950-9232. PMID 11002417.
  42. ^ Devin A, Lin Y, Yamaoka S, Li Z, Karin M (June 2001). "The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF". Mol. Cell. Biol. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. ISSN 0270-7306. PMC 87061. PMID 11359906.
  43. ^ Li S, Wang L, Dorf ME (January 2009). "PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination". Mol. Cell. 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425.

See also

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "IκB kinase". More...

IκB kinase Edit Wikipedia article

IkappaB kinase
Identifiers
EC number2.7.11.10
CAS number159606-08-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

The IκB kinase (IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation.[1]

The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of kappa B) protein inactivates the NF-κB transcription factor by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.[2][3][4] Specifically, IKK phosphorylates the inhibitory IκBα protein.[5] This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free, migrates into the nucleus and activates the expression of at least 150 genes; some of which are anti-apoptotic.

Catalyzed reaction

In enzymology, an IκB kinase (EC 2.7.11.10) is an enzyme that catalyzes the chemical reaction:

ATP + IκB protein ADP + IκB phosphoprotein

Thus, the two substrates of this enzyme are ATP and IκB protein, whereas its two products are ADP and IκB phosphoprotein.

This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases).[citation needed] The systematic name of this enzyme class is ATP:[IκB protein] phosphotransferase.

Structure

The IκB kinase complex is composed of three subunits each encoded by a separate gene:

The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.

The IKK-α and IKK-β kinase subunits are homologous in structure, composed of a kinase domain, as well as leucine zipper and helix-loop-helix dimerization domains, and a carboxy-terminal NEMO-binding domain (NBD).[6] Mutational studies have revealed the identity of the NBD amino acid sequence as leucine-aspartate-tryptophan-serine-tryptophan-leucine, encoded by residues 737-742 and 738-743 of IKK-α and IKK-β, respectively.[7] The regulatory IKK-γ subunit, or NEMO, is composed of two coiled coil domains, a leucine zipper dimerization domain, and a zinc finger-binding domain.[6] Specifically, the NH2-terminus of NEMO binds to the NBD sequences on IKK-α and IKK-β, leaving the rest of NEMO accessible for interacting with regulatory proteins.[7]

conserved helix-loop-helix ubiquitous kinase
Identifiers
SymbolCHUK
Alt. symbolsIKK-alpha, IKK1, TCF16
NCBI gene1147
HGNC1974
OMIM600664
RefSeqNM_001278
UniProtO15111
Other data
EC number2.7.11.10
LocusChr. 10 q24-q25
inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Identifiers
SymbolIKBKB
Alt. symbolsIKK-beta, IKK2
NCBI gene3551
HGNC5960
OMIM603258
RefSeqNM_001556
UniProtO14920
Other data
EC number2.7.11.10
LocusChr. 8 p11.2
inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
Identifiers
SymbolIKBKG
Alt. symbolsIKK-gamma, NEMO, IP2, IP1
NCBI gene8517
HGNC5961
OMIM300248
RefSeqNM_003639
UniProtQ9Y6K9
Other data
LocusChr. X q28

Function

IκB kinase activity is essential for activation of members of the nuclear factor-kB (NF-κB) family of transcription factors, which play a fundamental role in lymphocyte immunoregulation.[6][8] Activation of the canonical, or classical, NF-κB pathway begins in response to stimulation by various pro-inflammatory stimuli, including lipopolysaccharide (LPS) expressed on the surface of pathogens, or the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). Following immune cell stimulation, a signal transduction cascade leads to the activation of the IKK complex, an event characterized by the binding of NEMO to the homologous kinase subunits IKK-α and IKK-β. The IKK complex phosphorylates serine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to its ubiquitination and subsequent degradation by the proteasome.[5] Degradation of IκBα releases the prototypical p50-p65 dimer for translocation to the nucleus, where it binds to κB sites and directs NF-κB-dependent transcriptional activity.[8] NF-κB target genes can be differentiated by their different functional roles within lymphocyte immunoregulation and include positive cell-cycle regulators, anti-apoptotic and survival factors, and pro-inflammatory genes. Collectively, activation of these immunoregulatory factors promotes lymphocyte proliferation, differentiation, growth, and survival.[9]

Regulation

Activation of the IKK complex is dependent on phosphorylation of serine residues within the kinase domain of IKK-β, though IKK-α phosphorylation occurs concurrently in endogenous systems. Recruitment of IKK kinases by the regulatory domains of NEMO leads to the phosphorylation of two serine residues within the activation loop of IKK-β, moving the activation loop away from the catalytic pocket, thus allowing access to ATP and IκBα peptide substrates. Furthermore, the IKK complex is capable of undergoing trans-autophosphorylation, where the activated IKK-β kinase subunit phosphorylates its adjacent IKK-α subunit, as well as other inactive IKK complexes, thus resulting in high levels of IκB kinase activity. Following IKK-mediated phosphorylation of IκBα and the subsequent decrease in IκB abundance, the activated IKK kinase subunits undergo extensive carboxy-terminal autophosphorylation, reaching a low activity state that is further susceptible to complete inactivation by phosphatases once upstream inflammatory signaling diminishes.[5]

Deregulation and disease

Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states.[5][6][7][8][9][10] Increased NF-κB activity as a result of constitutive IKK-mediated phosphorylation of IκBα has been observed in the development of atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis.[8][10] Specifically, constitutive NF-κB activity promotes continuous inflammatory signaling at the molecular level that translates to chronic inflammation phenotypically. Furthermore, the ability of NF-κB to simultaneously suppress apoptosis and promote continuous lymphocyte growth and proliferation explains its intimate connection with many types of cancer.[8][9]

Clinical significance

This enzyme participates in 15 pathways related to metabolism: MapK signaling, apoptosis, Toll-like receptor signaling, T-cell receptor signaling, B-cell receptor signaling, insulin signaling, adipokine signaling, Type 2 diabetes mellitus, epithelial cell signaling in helicobacter pylori, pancreatic cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia, and small cell lung cancer.

Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[11] The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[11][12]

References

  1. ^ Häcker H, Karin M (October 2006). "Regulation and function of IKK and IKK-related kinases". Sci. STKE. 2006 (357): re13. doi:10.1126/stke.3572006re13. PMID 17047224.
  2. ^ Jacobs MD, Harrison SC (1998). "Structure of an IkappaBalpha/NF-kappaB complex". Cell. 95 (6): 749–58. doi:10.1016/S0092-8674(00)81698-0. PMID 9865693.
  3. ^ Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (1997). "Identification and characterization of an IkappaB kinase". Cell. 90 (2): 373–83. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310.
  4. ^ Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A (1997). "IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation". Science. 278 (5339): 860–6. doi:10.1126/science.278.5339.860. PMID 9346484.
  5. ^ a b c d Karin M (1999). "How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex". Oncogene. 18 (49): 6867–74. doi:10.1038/sj.onc.1203219. PMID 10602462.
  6. ^ a b c d Ghosh S, Hayden M (November 2008). "New regulators of NF-κB in inflammation". Nat. Rev. Immunol. 8 (11): 837–48. doi:10.1038/nri2423. PMID 18927578.
  7. ^ a b c May MJ, D'acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex". Science. 289 (5484): 1550–54. doi:10.1126/science.289.5484.1550. PMID 10968790.
  8. ^ a b c d e Strickland I, Ghosh S (November 2006). "Use of cell permeable NBD peptides for suppression of inflammation". Ann Rheum Dis. 65 (Suppl 3): iii75–iii82. doi:10.1136/ard.2006.058438. PMC 1798375. PMID 17038479.
  9. ^ a b c Jost PJ, Ruland J (April 2007). "Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications". Blood. 109 (7): 2700–7. doi:10.1182/blood-2006-07-025809. PMID 17119127.
  10. ^ a b Tak PP, Firestein GS (January 2001). "NF-κB: a key role in inflammatory diseases". J. Clin. Invest. 107 (1): 7–11. doi:10.1172/JCI11830. PMC 198552. PMID 11134171.
  11. ^ a b Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
  12. ^ "SAR113945 published clinical trials".

Further reading

  • Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell. 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. PMID 9346241.
  • Viatour P, Merville MP, Bours V, Chariot A (2005). "Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation". Trends Biochem. Sci. 30 (1): 43–52. doi:10.1016/j.tibs.2004.11.009. PMID 15653325.

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "IκB kinase". More...

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

IQBAL scaffold dimerization domain Provide feedback

This is the C-terminal scaffold dimerization domain (SDD) found in inhibitor of nuclear factor kappa-B kinase subunit beta IKBKB ( EC:2.7.11.10) [1]. IKK2 also known as IKBKB is one of the core component of IKB kinases (IKK). IKB kinase (IKK) is an enzyme that quickly becomes active in response to diverse stresses on a cell. The SDD consists primarily of two long alpha-helices [2].

Literature references

  1. Liu S, Misquitta YR, Olland A, Johnson MA, Kelleher KS, Kriz R, Lin LL, Stahl M, Mosyak L;, J Biol Chem. 2013;288:22758-22767.: Crystal structure of a human IkappaB kinase beta asymmetric dimer. PUBMED:23792959 EPMC:23792959

  2. Polley S, Huang DB, Hauenstein AV, Fusco AJ, Zhong X, Vu D, Schrofelbauer B, Kim Y, Hoffmann A, Verma IM, Ghosh G, Huxford T;, PLoS Biol. 2013;11:e1001581.: A structural basis for IkappaB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation. PUBMED:23776406 EPMC:23776406


This tab holds annotation information from the InterPro database.

No InterPro data for this Pfam family.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(13)
Full
(331)
Representative proteomes UniProt
(641)
NCBI
(1199)
Meta
(0)
RP15
(46)
RP35
(107)
RP55
(210)
RP75
(262)
Jalview View  View  View  View  View  View  View  View   
HTML View  View               
PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(13)
Full
(331)
Representative proteomes UniProt
(641)
NCBI
(1199)
Meta
(0)
RP15
(46)
RP35
(107)
RP55
(210)
RP75
(262)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(13)
Full
(331)
Representative proteomes UniProt
(641)
NCBI
(1199)
Meta
(0)
RP15
(46)
RP35
(107)
RP55
(210)
RP75
(262)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

This family is new in this Pfam release.

Seed source: ECOD:EUF01189
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: El-Gebali S
Number in seed: 13
Number in full: 331
Average length of the domain: 252.00 aa
Average identity of full alignment: 58 %
Average coverage of the sequence by the domain: 37.30 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.2 25.3
Noise cut-off 21.8 24.5
Model length: 276
Family (HMM) version: 1
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

Align selected sequences to HMM

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IKBKB_SDD domain has been found. There are 35 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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