Structure of NFAT1 bound as a dimer to the HIV-1 LTR κB element

Giffin, Michael J.; Stroud, James C.; Bates, D.L.; Koenig, Konstanze D von; Hardin, John W.; Chen, Lin

doi:10.1038/nsb981

Cited by 98 publications

(128 citation statements)

References 44 publications

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“…CSL, which is related structurally to the Rel-homology family of transcription factors, has three domains, and the linkers connecting the domains may be the source of flexibility. In canonical Rel-family members like nuclear factor of activated T cells 1 (NFAT1), flexibility in the linkers connecting the RHR-N and RHR-C domains enables adaptation to different environments to bind different DNA sequences and cooperate with other factors on DNA (32)(33)(34). The ability of the C. elegans homolog LAG-1 to undergo a domain shift upon complexation with ICN and MAML (14) substantiates the notion that the worm CSL protein also can adapt to different environments (for example, different spacer lengths between paired sites) by domain movement without losing the ability to bind consensus site DNA, although the divergence of the C. elegans notches (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Nam

Sliz

Pear

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

157

218

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Notch receptors control differentiation and contribute to pathologic states such as cancer by interacting directly with a transcription factor called CSL (for CBF-1/Suppressor of Hairless/Lag-1) to induce expression of target genes. A number of Notch-regulated targets, including genes of the hairy/enhancer-of-split family in organisms ranging from Drosophila to humans, are characterized by paired CSL-binding sites in a characteristic head-to-head arrangement. Using a combination of structural and molecular approaches, we establish here that cooperative formation of dimeric Notch transcription complexes on promoters with paired sites is required to activate transcription. Our findings identify a mechanistic step that can account for the exquisite sensitivity of Notch target genes to variation in signal strength and developmental context, enable new strategies for sensitive and reliable identification of Notch target genes, and lay the groundwork for the development of Notch pathway inhibitors that are active on target genes containing paired sites.

show abstract

Section: Discussionmentioning

confidence: 99%

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Nam

Sliz

Pear

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

157

218

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“…6D). The model assumes that the linker between the N-and C-terminal domains of the NFAT RHR assumes an extended conformation similar to those observed in complexes of an NFAT1 dimer bound to palindromic NF B-like DNA elements (38,39), thus permitting interaction of the C-terminal RHR domain (RHR-C) with the Ig domain of T-bet. In the middle of the complex, the C-terminal helix (H4) of T-bet could form favorable interactions with the Fos helix (Fig.…”

Section: ј Cns)mentioning

confidence: 99%

A Distal Enhancer in the Interferon-γ (IFN-γ) Locus Revealed by Genome Sequence Comparison

Lee

Avni

Chen

et al. 2004

Journal of Biological Chemistry

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128

133

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Large-scale cross-species DNA sequence comparison has become a powerful tool to identify conserved cisregulatory modules of genes. However, bioinformatic analysis alone cannot reveal how an evolutionarily conserved region regulates gene expression: whether it functions as an enhancer, silencer, or insulator; whether its function is cell-type restricted; and whether biologically relevant transcription factors bind to the element. Here we combine bioinformatics with wet-lab techniques to illustrate a general and systematic method of identifying functional conserved regulatory regions of genes. We applied this approach to the interferongamma (IFN-␥) gene. Comparison of human and mouse IFN-␥ reveals a highly conserved non-coding sequence located ϳ5 kb 5 of the transcription start site. This region coincides with constitutive and inducible DNase I hypersensitivity sites present in IFN-␥-producing Th1 cells but not in Th2 cells that do not produce IFN-␥. Histone methylation at the 5 conserved non-coding sequences indicates a more accessible chromatin structure in Th1 cells compared with Th2 cells. This element binds two transcription factors known to be essential for IFN-␥ expression: nuclear factor of activated T cells, an inducible transcription factor, and T-box protein expressed in T cells, a cell lineage-restricted transcription factor. Together, these findings identify a highly conserved distal enhancer in the IFN-␥ cytokine locus and validate our approach as a successful method to detect cis-regulatory elements.Gene transcription is regulated by the binding of transacting factors to short DNA elements (5-8 bp) contained within larger blocks of cis-regulatory sequences (100 -400 bp) (1). An important cis-regulatory module is located at the proximal promoter, which specifies the site of transcriptional initiation. In metazoans, however, the levels and cell specificity of gene expression are generally controlled by distal regulatory modules (enhancers and silencers) that may be located in introns or intergenic regions and that potentiate or repress gene transcription. Typically, multiple regulatory modules are associated with a single gene, and different combinations of modules are utilized to control gene expression in different cell types at different developmental stages or under different conditions of stimulation (1). A characteristic feature of the modules is the presence of clustered binding sites for relevant transcription factors. For instance, the promoters and distal enhancers of genes expressed in muscle are enriched in binding sites for muscle-specific transcription factors, including Mef-2, Myf, and SRF (2, 3).Recently, there has been much interest in the possibility of using comparative sequence analysis to identify gene regulatory elements. In mammals, only about 5% of the genome is estimated to encode proteins. The bulk of non-coding DNA is not conserved between species, but long-range sequence comparisons reveal islands of highly conserved non-coding sequences (CNS) 1 in a sea of non-conserved DN...

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“…Jurkat cells were transfected DNA contacts and is also involved in interactions with other transcription factors (13)(14)(15)(16)(17)(18). In resting T cells, NFAT proteins reside in the cytosol in a highly phosphorylated state.…”

mentioning

confidence: 99%

Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

Soto-Nieves¹,

Puga²,

Abe³

et al. 2009

J Cell Biol

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Structure of NFAT1 bound as a dimer to the HIV-1 LTR κB element

Cited by 98 publications

References 44 publications

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

A Distal Enhancer in the Interferon-γ (IFN-γ) Locus Revealed by Genome Sequence Comparison

Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

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