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The Structural Biology of NF-κB

  • Chapter
Nuclear Factor кB

Abstract

The mechanisms underlying activation and DNA binding of the transcription factor NF-κB are central to our understanding of the cellular response to stress, development and apoptosis, among other key physiological processes (Baeuerle & Henkel, 1994; Siebenlist et al., 1994; Baeuerle & Baltimore, 1996; Baldwin, 1996; Ghosh et al., 1998; Gilmore, 1999; Silverman & Maniatis, 2001). Central to gene regulation by NF-κB is its release from inhibition by IκB and subsequent recognition of specific promoters of inducible genes. Three-dimensional structures of NF-κB proteins in complex with κB DNA or IκB inhibitors have provided new insights into the complexities of the NF-κB-signaling pathways and NF-κB-mediated gene regulation. In this review, we shall focus on the structural features of NF-κB/DNA and IκB/NF-κB complexes, as well as on the relation of these structures to biological function.

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References

  • Baeuerle PA & Baltimore D (1988) IκB: a specific inhibitor of the NF-κB transcription factor. Science 242: 540–546.

    Article  PubMed  CAS  Google Scholar 

  • Baeuerle PA & Baltimore D (1996) NF-κB: ten years after. Cell 87: 13–20.

    Article  PubMed  CAS  Google Scholar 

  • Baeuerle PA & Henkel T (1994) Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12: 141–179.

    Article  PubMed  CAS  Google Scholar 

  • Baldwin AS (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14: 649–683.

    Article  PubMed  CAS  Google Scholar 

  • Barroga CF, Stevenson JK, Schwarz EM & Verma IM (1995) Constitutive phosphorylation of IκBα by casein kinase II. Proc. Natl. Acad. Sci. USA 92: 7637–7641.

    Article  PubMed  CAS  Google Scholar 

  • Becker S, Groner B & Müller CW (1998) Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394: 145–151.

    Article  PubMed  CAS  Google Scholar 

  • Bork P (1993) Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally? Proteins 17: 363–374.

    Article  PubMed  CAS  Google Scholar 

  • Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K & Siebenlist U (1993) The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers. Cell 72: 729–739.

    Article  PubMed  CAS  Google Scholar 

  • Bundy DL & McKeithan TW (1997) Diverse effects of Bcl-3 phosphorylation on its modulation of NF-κB p52 homodimer binding to DNA. J. Biol. Chem. 272: 33132–33139.

    Article  PubMed  CAS  Google Scholar 

  • Chen FE, Huang D-B, Chen Y-Q & Ghosh G (1998a) Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA. Nature 391: 410–413.

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Vinkemeier U, Hao Y, Jeruzalmi D, Darnell JE & Kuriyan J (1998b) Crystal structure of a tyrosine phosphorylated Stat-1 dimer bound to DNA. Cell 93: 827–839.

    Article  PubMed  CAS  Google Scholar 

  • Chen Y-Q, Ghosh S & Ghosh G (1998c) A novel DNA recognition mode by the NF-κB p65 homodimer. Nature Struct. Biol. 5: 67–73.

    Article  PubMed  Google Scholar 

  • Chen Y-Q, Sengchanthalangsy LL, Hackett A & Ghosh G (2000) NF-κB p65 (RelA) homodimer uses distinct mechanisms to recognize DNA targets. Structure 8: 419–428.

    Article  PubMed  CAS  Google Scholar 

  • Cramer P, Larson CJ, Verdine GL & Müller CW (1997) Structure of the human NF-κB p52 homodimer-DNA complex at 2.1 Å resolution. EMBO J. 16: 7078–7090.

    Article  PubMed  CAS  Google Scholar 

  • Cramer P, Varrot A, Barillas-Mury C, Kafatos FC & Müller CW (1999) Structure of the specificity domain of the Dorsal homologue Gambifl bound to DNA. Structure 7: 841–852.

    Article  PubMed  CAS  Google Scholar 

  • Cross SL, Halden NF, Lenardo MJ & Leonard WJ (1989) Functionally distinct NF-κB binding sites in the immunoglobulin κ and IL-2 receptor α chain genes. Science 244: 466–469.

    Article  PubMed  CAS  Google Scholar 

  • Darnell JE (1997) Stats and gene regulation. Science 277: 1630–1635.

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Hatzubai A, Andersen JS, Ben-Shushan E, Fisher GZ, Yaron A, Bauskin A, Mercurio F, Mann M & Ben-Neriah Y (2002) Pseudosubstrate regulation of the SCF/β-TrCP ubiquitin ligase by hnRNP-u. Genes Dev. 16: 439–451.

    Article  PubMed  CAS  Google Scholar 

  • Dobrzanski P, Ryseck R-P & Bravo R (1993) Both N-and C-terminal domains of RelB are required for full transactivation: role of the N-terminal leucine zipper-like motif. Mol. Cell. Biol. 13: 1572–1582.

    PubMed  CAS  Google Scholar 

  • Ernst MK, Dunn LL & Rice NR (1995) The PEST-like sequence of IκBα is responsible for inhibition of DNA binding but not for cytoplasmic retention of c-Rel or RelA homodimers. Mol. Cell. Biol. 15: 872–882.

    PubMed  CAS  Google Scholar 

  • Escalante CR, Shen LY, Thanos D & Aggarwal AK (2002) Structure of NF-κB p65 (RelA) p50/p65 heterodimer bound to the PRDII DNA element from the interferon-β promoter. Structure 10: 383–391.

    Article  PubMed  CAS  Google Scholar 

  • Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K & Siebenlist U (1992) The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-κB-mediated inhibition. Nature 359: 339–342.

    Article  PubMed  CAS  Google Scholar 

  • Fujita T, Nolan GP, Liou H-C, Scott ML & Baltimore D (1993) The candidate proto-oncogene Bcl-3 encodes a transcriptional coactivator that activates through NF-κB p50 homodimers. Genes Dev. 7: 1354–1363.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh G, Van Duyne G, Ghosh S & Sigler PB (1995) Structure of NF-κB p50 homodimer bound to a kB site. Nature 373: 303–310.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh S, May MJ & Kopp EB (1998) NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16: 225–260.

    Article  PubMed  CAS  Google Scholar 

  • Gilmore TD (1999) The Rel/NF-κB signal transduction pathway. Introduction. Oncogene 18: 6842–6844.

    CAS  Google Scholar 

  • Groves MR & Barford D (1999) Topological characteristics of helical repeat proteins. Curr. Opin. Struct. Biol. 9: 383–389.

    Article  PubMed  CAS  Google Scholar 

  • Hart DJ, Speight RE, Sutherland JD & Blackburn JM (2001) Analysis of the NF-κB p50 dimerinterface by diversity screening. J. Mol. Biol. 310: 563–575.

    Article  PubMed  CAS  Google Scholar 

  • Hatada EN, Nieters A, Wulczyn FG, Naumann M, Meyer R, Nucifora G, McKeithan TW & Scheidereit C (1992) The ankyrin repeat domains of the NF-κB precursor p105 and the proto-oncogene Bcl-3 act as specific inhibitors of NF-κB DNA binding. Proc. Natl. Acad. Sci. 89: 2489–2493.

    Article  PubMed  CAS  Google Scholar 

  • Heissmeyer V, Krappmann D, Hatada EN & Scheidereit C (2001) Shared pathways of IκB kinase-induced SCF/βTrCP-mediated ubiquitination and degradation for the NF-κB precursor p105 and IκBα. Mol. Cell. Biol. 21: 1024–1035.

    Article  PubMed  CAS  Google Scholar 

  • Huang D-B, Chen Y-Q, Ruetsche M, Phelps CB & Ghosh G (2001) X-ray crystal structure of proto-oncogene product c-Rel bound to the CD28 response element of IL-2. Structure 9: 669–678.

    Article  PubMed  CAS  Google Scholar 

  • Huang D-B, Huxford T, Chen Y-Q & Ghosh G (1997) The role of DNA in the mechanism of NF-κB dimer formation: crystal structures of the dimerization domains of the p50 and p65 subunits. Structure 5: 1427–1436.

    Article  PubMed  CAS  Google Scholar 

  • Huang TT, Kudo N, Yoshida M & Miyamoto S (2000) A nuclear export signal in the N-terminal regulatory domain of IκBα controls cytoplasmic localization of inactive NF-κB/IκBcα complexes. Proc. Natl. Acad. Sci. USA 97: 1014–1019.

    Article  PubMed  CAS  Google Scholar 

  • Huxford T, Huang D-B, Malek S & Ghosh G (1998) The crystal structure of the IκBκ/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell 95: 759–770.

    Article  PubMed  CAS  Google Scholar 

  • Inoue JI, Kerr LD, Kakizuka A & Verma IM (1992) IκBγ, a 70 kD protein identical to the C-terminal half of p110 NF-κB: a new member of the IκB family. Cell 68: 1109–1120.

    Article  PubMed  CAS  Google Scholar 

  • Jacobs MD & Harrison SC (1998) Structure of an IκBκ/NF-κB complex. Cell 95: 749–758.

    Article  PubMed  CAS  Google Scholar 

  • Jacobson EM, Li P, Leon-Del-Rio A, Rosenfeld MG & Aggarwal AK (1997) Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility. Genes Dev. 11: 198–212.

    Article  PubMed  CAS  Google Scholar 

  • Johnson C, Van Antwerp D & Hope TJ (1999) An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα. EMBO J. 18: 6682–6693.

    Article  PubMed  CAS  Google Scholar 

  • Karin M & Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18: 621–663.

    Article  PubMed  CAS  Google Scholar 

  • Kitamura H, Kanehira K, Okita K, Morimatsu M & Saito M (2000) MAIL, a novel nuclear IκB protein that potentiates LPS-induced IL-6 production. FEBS Lett. 485: 53–56.

    Article  PubMed  CAS  Google Scholar 

  • Kushner DB & Ricciardi RP (1999) Reduced phosphorylation of p50 is responsible for diminished NF-κB binding to the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells. Mol. Cell. Biol. 19: 2169–2179.

    PubMed  CAS  Google Scholar 

  • Lehming N, McGuire S, Brickman JM & Ptashne M (1995) Interactions of a Rel protein with its inhibitor. Proc. Natl. Acad. Sci. USA 92: 10242–10246.

    Article  PubMed  CAS  Google Scholar 

  • Leonard WJ & O’Shea JJ (1998). Jaks and Stats: biological implications. Annu Rev. Immunol. 16: 293–322.

    Article  PubMed  CAS  Google Scholar 

  • Liou HC, Nolan GP, Ghosh S, Fujita T & Baltimore D (1992) The NF-κB p50 precursor, p105, contains an internal IκB-like inhibitor that preferentially inhibits p50. EMBO J. 11: 3003–3009.

    PubMed  CAS  Google Scholar 

  • Liu J, Sodeoka M, Lane WS & Verdine GL (1994) Evidence for a non-a-helical DNA-binding motif in the Rel homology region. Proc. Natl. Acad. Sci. USA 91: 908–912.

    Article  PubMed  CAS  Google Scholar 

  • Malek S, Chen Y, Huxford T & Ghosh G (2001) IκBβ, but not IκBα, functions as a classical cytoplasmic inhibitor of NF-κB dimers by masking both NF-κB nuclear localization sequences in resting cells. J. Biol. Chem. 276: 45225–45235.

    Article  PubMed  CAS  Google Scholar 

  • McElhinny JA, Trushin SA, Bren GD, Chester N & Paya CV (1996) Casein kinase II phosphorylates IκBα at S283, S289, S293, and T291 and is required for its degradation in vitro. Mol. Cell. Biol. 16: 899–906.

    PubMed  CAS  Google Scholar 

  • Mercurio F, Didonato JA, Rosette C & Karin M (1993) P105 and p98 precursor proteins play an active role in NF-KB-mediated signal transduction. Genes Dev. 7: 705–718.

    Article  PubMed  CAS  Google Scholar 

  • Michaely P & Vennett V (1992) The ANK repeat: a ubiquitous motif involved in macromolecular recognition. Trends Cell. Biol. 2: 127–130.

    Article  PubMed  CAS  Google Scholar 

  • Michel F, Soler-Lopez M, Petosa C, Cramer P, Siebenlist U & Müller CW (2001) Crystal structure of the ankyrin repeat domain of Bcl-3: a unique member of the kB protein family. EMBO J. 20: 6180–6190.

    Article  PubMed  CAS  Google Scholar 

  • Müller CW, Rey FA, Sodeoka M, Verdine GL & Harrison SC (1995) Structure of the NF-κB p50 homodimer bound to DNA. Nature 373: 311–317.

    Article  PubMed  Google Scholar 

  • Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18: 6853–6866.

    Article  PubMed  CAS  Google Scholar 

  • Phelps CB, Sengchanthalangsy LL, Malek S & Ghosh G (2000) Mechanism of κB DNA binding by Rel/NF-κB dimers. J. Biol. Chem. 275: 24392–24399.

    Article  PubMed  CAS  Google Scholar 

  • Plaksin D, Baeuerle PA & Eisenbach L (1993) KBF1 (p50 NF-κB homodimer) acts as a repressor of H-2K-b gene expression in metastatic tumor cells. J. Exp. Med. 177: 1651–1662.

    Article  PubMed  CAS  Google Scholar 

  • Rao A, Luo C & Hogan PG (1997) Transcription factors of the NF-AT family: regulation and function. Annu. Rev. Immunol. 15: 707–747.

    Article  PubMed  CAS  Google Scholar 

  • Rice NR, Mackichan ML & Isräel A (1992) The precursor of NF-κB p50 has IκB-like functions. Cell 71: 243–253.

    Article  PubMed  CAS  Google Scholar 

  • Rogers S, Wells R & Rechsteiner M (1986) Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234: 364–368.

    Article  PubMed  CAS  Google Scholar 

  • Ryseck R-P, Novotny J & Bravo R (1995) Characterization of elements determining the dimerization properties of RelB and p50. Mol. Cell. Biol. 15: 3100–3109.

    PubMed  CAS  Google Scholar 

  • Ryseck RP, Bull P, Takamiya M, Bours V, Siebenlist U, Dobrzanski P & Bravo R (1992) RelB, a new Rel family transcription activator that can interact with p50-NF-κB. Mol. Cell. Biol. 12: 674–684.

    PubMed  CAS  Google Scholar 

  • Sanjabi S, Hoffmann A, Liou H-C, Baltimore D & Smale ST (2000) Selective requirement for c-Rel during IL-12 p40 gene induction in macrophages. Proc. Natl. Acad. Sci. USA 97: 12705–12710.

    Article  PubMed  CAS  Google Scholar 

  • Schwarz EM, Van Antwerp D & Verma IM (1996) Constitutive phosphorylation of IκBα by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IκBα. Mol. Cell. Biol. 16: 3554–3559.

    PubMed  CAS  Google Scholar 

  • Sedgwick SG & Smerdon SJ (1999) The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem. Sci. 24: 311–316.

    Article  PubMed  CAS  Google Scholar 

  • Sengchanthalangsy LL, Datta S, Huang D-B, Anderson E, Braswell EH & Ghosh G (1999) Characterization of the dimer interface of transcription factor NF-κB p50 homodimer. J. Mol. Biol. 289: 1029–1040.

    Article  PubMed  CAS  Google Scholar 

  • Shiina T, Morimatsu M, Kitamura H, Ito T, Kidou S, Matsubara K, Matsuda Y, Saito M & Syuto B (2001) Genomic organization, chromosomal localization, and promoter analysis of the mouse MAIL gene. Immunogenetics 53: 649–655.

    Article  PubMed  CAS  Google Scholar 

  • Siebenlist U, Franzoso G & Brown K (1994). Structure, regulation and function of NF-κB. Annu. Rev. Immunol. 12: 405–455.

    Google Scholar 

  • Silverman N & Maniatis T (2001) NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15: 2321–2342.

    Article  PubMed  CAS  Google Scholar 

  • Simeonidis S, Liang S, Chen G & Thanos D (1997) Cloning and functional characterization of mouse IκBε. Proc. Natl. Acad. Sci. USA 94: 14372–14377.

    Article  PubMed  CAS  Google Scholar 

  • Tam WF, Lee LH, Davis L & Sen R (2000) Cytoplasmic sequestration of Rel proteins by IκBα requires Crml-dependent nuclear export. Mol. Cell. Biol. 20: 2269–2284.

    Article  PubMed  CAS  Google Scholar 

  • Tam WF & Sen R (2001) IκB family members function by different mechanisms. J. Biol. Chem. 276: 7701–7704.

    Article  PubMed  CAS  Google Scholar 

  • Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P & Ghosh S (1995) IκBβ regulates the persistent response in a biphasic activation of NF-κB. Cell 80: 573–582.

    Article  PubMed  CAS  Google Scholar 

  • Tran K, Merika M & Thanos D (1997) Distinct functional properties of IκBα and IκBβ. Mol. Cell. Biol. 17: 5386–5399.

    PubMed  CAS  Google Scholar 

  • Verma IM, Stevenson K, Schwarz EW, Van Antwerp D & Miyamoto S (1995) Rel/NF-κB/κB family: intimate tales of association and dissociation. Genes Dev. 9: 2723–2735.

    Article  PubMed  CAS  Google Scholar 

  • Whiteside ST, Epinat J-C, Rice NR & Isräel A (1997) IκBε, a novel member of the kB family, controls RelA and c-Rel NF-κB activity. EMBO J. 16: 1413–1426.

    Article  PubMed  CAS  Google Scholar 

  • Whiteside ST & Isräel A (1997) IκB proteins: structure, function and regulation. Semin. Canc. Biol. 8: 75–82.

    Article  CAS  Google Scholar 

  • Wulczyn FG, Naumann M & Scheidereit C (1992) Candidate proto-oncogene Bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-κB. Nature 358: 597–599.

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki S, Muta T & Takeshige K (2001) A novel IκB protein, IκBζ, induced by proinflammatory stimuli, negatively regulates NF-κB in the nuclei. J. Biol. Chem. 276: 27657–27662.

    Article  PubMed  CAS  Google Scholar 

  • Zabel U & Baeuerle PA (1990) Purified human IκB can rapidly dissociate the complex of the NF-κB transcription factor with its cognate DNA. Cell 61: 255–266.

    Article  PubMed  CAS  Google Scholar 

  • Zabel U, Henkel T, Dos Santos Silva M & Baeuerle PA (1993) Nuclear uptake control of NF-κB by MAD-3, an IκB protein present in the nucleus. EMBO J. 12: 201–211.

    PubMed  CAS  Google Scholar 

  • Zhong H, May MJ, Jimi E & Ghosh S (2002) The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell 9: 625–636.

    Article  PubMed  CAS  Google Scholar 

  • Zhong H, Voll RE & Ghosh S (1998) Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell 1: 661–671.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mc 0359, La Jolla, CA, 92093, USA

    T. Huxford & G. Ghosh

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  1. T. Huxford
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  2. G. Ghosh
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  1. Department for Molecular Biomedical Research, Unit for Molecular Signal Transduction in Inflammation, Ghent University and Flanders Interuniversity Institute for Biotechnology, K.L. Ledeganckstraat 35, 9000, Ghent, Belgium

    Rudi Beyaert

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Huxford, T., Ghosh, G. (2003). The Structural Biology of NF-κB. In: Beyaert, R. (eds) Nuclear Factor кB. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-0163-2_8

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  • DOI: https://doi.org/10.1007/978-94-010-0163-2_8

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-3983-3

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