Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding

Gajiwala, K.S.; Chen, Hua; Cornille, Fabrice; Roques, Bernárd P.; Reith, Walter; Mach, Bernard; Burley, S.K.

doi:10.1038/35002634

Cited by 302 publications

(285 citation statements)

References 25 publications

(32 reference statements)

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“…2d). The W1 loop-mediated DNA-recognizing mechanism of PHF1 EH WH is different from other known winged-helix motifs, among which the HNF-3γ winged-helix motif recognizes DNA mainly through the third α-helix 19 , while the hRFX1 winged-helix motif makes sequence-specific contacts with the target DNA through both the third α-helix and the W1 loop 22 (Extended Data Fig. 3c, d, e).…”

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confidence: 93%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

254

323

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The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci4–13. Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. In this study, we solved the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We found that the extended homologous (EH) regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a manner completely different from the canonical winged-helix motif-DNA recognition. We further showed that the PCL EH domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic cells. Our research provides the first direct evidence demonstrating that PCLs are critical for PRC2 recruitment to CpG islands, thereby further clarifying their roles in transcriptional regulation in vivo.

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mentioning

confidence: 93%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

254

323

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“…Helix H3, often called the recognition helix, is very likely involved in DNA binding. Comparisons of crystallographic structures of DNA-bound winged-helix transcription factors (14,16,17), however, show a substantial variation in DNA positioning and mode of DNA binding. Thus, it may be risky to derive a model for DNA-GH5 interactions by assuming a specific mode of binding, such as insertion of the recognition helix into the DNA major groove (18).…”

mentioning

confidence: 99%

Complex of linker histone H5 with the nucleosome and its implications for chromatin packing

Фан

Roberts

2006

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

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Linker histones are essential for chromatin filament formation, and they play key roles in the regulation of gene expression. Despite the determination of structures of the nucleosome and linker histones, the location of the linker histone on the nucleosome is still a matter of debate. Here we show by computational docking that the globular domain of linker histone variant H5 (GH5) has three distinct DNA-binding sites, through which GH5 contacts the DNA at the nucleosome dyad and the linker DNA strands entering and exiting the nucleosome. Our results explain the extensive mutagenesis and crosslinking data showing that side chains spread throughout the GH5 surface interact with nucleosomal DNA. The nucleosome DNA contacts positively charged side chains that are conserved within the linker histone family, indicating that our model extends to linker histone-nucleosome interactions in general. Furthermore, our model provides a structural mechanism for formation of a dinucleosome complex specific to the linker histone H5, explaining its efficiency in chromatin compaction and transcription regulation. Thus, this work provides a basis for understanding how structural differences within the linker histone family result in functional differences, which in turn are important for gene regulation.computational docking ͉ DNA-protein interactions ͉ DOT ͉ linker DNA ͉ winged-helix protein T he interaction of the linker histone with the nucleosome is an ongoing controversial issue (1-3). Histone H5 has been the focus of linker-histone-related studies in recent years. H5 consists of a central globular domain (GH5) that is essential for nucleosome binding and is flanked by basic N-and C-terminal tails (4). Binding of either H5 or GH5 to nucleosomes protects an additional 20 bp of linker DNA from micrococcal nuclease digestion (5). Early studies based on micrococcal nuclease digestion and DNase I footprinting proposed a symmetrical model in which GH5 contacts the dyad of the nucleosome and both the entering and exiting DNA duplexes (also called DNA arms) (6, 7). A ''bridging'' model was later proposed based on experiments that mapped the binding site of GH5 on mixedsequence chicken chromatosomes by conjugating a crosslinking reagent to specific Ser-to-Cys substitutions (8). In this model, GH5 forms a bridge between one DNA arm and the dyad. A radically different ''off-axis'' model was developed from studies on a DNA fragment containing the Xenopus borealis somatic 5S RNA gene (9). Based on this model, GH5 is positioned Ϸ65 bp away from the dyad and is bound inside the DNA superhelix. The bridging and off-axis models imply there may be two equivalent linker histone-binding sites per nucleosome (1), but a 1:1 ratio of linker histone and nucleosome is observed (10, 11).There have been multiple proposals for defining the DNAbinding sites on the linker histone. GH5 has a winged-helix fold (12), consisting of a three-helix bundle in which helices H2 and H3 are part of a helix-turn-helix motif that is followed by a ␤-hairpin, termed the ...

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“…This may allow the DNA-binding lobes of ligand-free XC1739 to act independently for binding to XC1739 marO. Because there are multiple modes of DNA binding within the winged-helix family of DNA-binding proteins, 11,12 the manner in which XC1739 binds to DNA remains to be determined. This is currently in progress.…”

Section: Methodsmentioning

confidence: 99%

The crystal structure of XC1739: A putative multiple antibiotic‐resistance repressor (MarR) from Xanthomonas campestris at 1.8 Å resolution

Chin

et al. 2006

Proteins

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Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding

Cited by 302 publications

References 25 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

Complex of linker histone H5 with the nucleosome and its implications for chromatin packing

The crystal structure of XC1739: A putative multiple antibiotic‐resistance repressor (MarR) from Xanthomonas campestris at 1.8 Å resolution

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