Structure of NF-κB p50/p65 Heterodimer Bound to the PRDII DNA Element from the Interferon-β Promoter

Escalante, Carlos; Shen, Leyi; Thanos, Dimitris; Aggarwal, Aneel K.

doi:10.1016/s0969-2126(02)00723-2

Cited by 66 publications

(66 citation statements)

References 38 publications

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“…X-ray structure determination of a p50:p65/RelA RHR heterodimer bound to kB DNA from the original k light chain gene promoter, which is identical to a kB sequence that is present in the promoter of HIV genome (5 0 -GGGAC T TTCC-3 0 ), served to confirm this speculation (Chen et al 1998a). Additional crystal structures of NF-kB p50: p65/RelA heterodimer bound to different kB DNA further support the basic rules of DNA half-site recognition developed from the homodimer:DNA structures (Berkowitz et al 2002;Escalante et al 2002).…”

Section: Nf-kb Dimerizationmentioning

confidence: 70%

A Structural Guide to Proteins of the NF- B Signaling Module

Huxford¹,

Ghosh

2009

Cold Spring Harbor Perspectives in Biology

111

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Section: Nf-kb Dimerizationmentioning

confidence: 70%

A Structural Guide to Proteins of the NF- B Signaling Module

Huxford¹,

Ghosh

2009

Cold Spring Harbor Perspectives in Biology

111

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“…Among these, Arg35 and Glu39 are known to be involved in the interaction with DNA bases, and Cys38 and Arg187 are involved in binding with the sugar phosphate backbone (Chen et al, 1998b;Escalante et al, 2002). Chain A denotes the p65 subunit; chain B denotes the p50 subunit; chain C denotes the IkBz chain.…”

Section: Discussionmentioning

confidence: 99%

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

Manavalan

Govindaraj

Lee

et al. 2010

J of Molecular Recognition

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IkBz (inhibitor of NF-kB (nuclear factor kB) z) is a nuclear protein induced upon stimulation of toll-like receptors (TLRs) and interleukin-1 receptor. Induced IkBz, especially its C-terminal ankyrin repeat domain (ARD), interacts with NF-kB in the nucleus, where it regulates the transcriptional activity of target genes. Recent studies have shown that human ARD of IkBz binds with p50/p65 heterodimer and inhibits the transcription of NF-kB regulated genes, whereas mouse ARD of IkBz binds with p50/p50 homodimer and exhibits transcriptional activation activity. Since human and mouse IkBz ARD are identical, it is unclear how IkBz can be a positive and negative regulator of NF-kB-mediated transcription. Therefore, we generated a structural model of IkBz ARD and constructed a detailed molecular dynamics (MD) simulation of IkBz in explicit solvent to investigate ARD flexibility. In addition, we used molecular docking to screen for potential sites of interaction between IkBz and the p50/p65 heterodimer and IkBz and the p50/p50 homodimer. The docking experiments revealed that the binding of IkBz ankyrin repeats with the p50/p65 N-terminal DNA binding domain prevents NF-kB-mediated transcriptional activation. Furthermore, the IkBz-p50 homodimer complex, which lacks Pro, Glu (and Asp), Ser and Thr (PEST motif), facilitated gene expression. These two different binding schemes of IkBz may be responsible for its opposite function, which is consistent with the currently available biochemical data. Moreover, our data implicate structurally highly flexible ARD residues as the prime contributors to this dual function.

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“…A strict sequence requirement for NF-nB inducibility is observed in the nB site within the IFN-h promoter (GGGAAATTCC), which when substituted by a closely related nB site from the Ign light gene enhancer (GGGACTTTCC) becomes nonresponsive to NF-nB activation (12). Structural studies revealed that differences in nB sequences of IFN-h and the Ign light chain gene enhancers contribute to structural changes in the NF-nB dimer/DNA complex, leading to altered gene expression (13,14). Leung et al (11) showed that the nB site sequence specifies which coactivators will result in productive interactions with bound NF-nB dimers.…”

Section: Introductionmentioning

confidence: 99%

Mullerian-Inhibiting Substance Induces Gro-β Expression in Breast Cancer Cells through a Nuclear Factor-κB–Dependent and Smad1-Dependent Mechanism

et al. 2007

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Mullerian-inhibiting substance (MIS), a transforming growth factor-B family member, activates the nuclear factor-KB (NF-KB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-B. Inhibiting NF-KB activation with a phosphorylation-deficient IKBA mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-B promoterdriven reporter expression and Gro-B mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-B mRNA, suggesting that regulation of Gro-B expression by MIS was dependent on activation of NF-KB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of KB-binding sequences within Gro-B, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-KB complex bound to the KB site of the Gro-B promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-B promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-KB signaling in which enhancement of NF-KB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the KB consensus site within the promoter. [Cancer Res 2007;67(6):2747-56]

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Structure of NF-κB p50/p65 Heterodimer Bound to the PRDII DNA Element from the Interferon-β Promoter

Cited by 66 publications

References 38 publications

A Structural Guide to Proteins of the NF- B Signaling Module

A Structural Guide to Proteins of the NF- B Signaling Module

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

Mullerian-Inhibiting Substance Induces Gro-β Expression in Breast Cancer Cells through a Nuclear Factor-κB–Dependent and Smad1-Dependent Mechanism

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