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The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B.

Zhang Y, Yang H, Guo X, Rong N, Song Y, Xu Y, Lan W, Zhang X, Liu M, Xu Y, Cao C - Protein Cell (2014)

Bottom Line: KDM5B is a histone H3K4me2/3 demethylase.The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear.Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.

ABSTRACT
KDM5B is a histone H3K4me2/3 demethylase. The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear. In this paper, we observed that PHD1KDM5B interacts with unmethylated H3K4me0. Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers. The disruption of this interaction by double mutations on the residues in the interface (L325A/D328A) decreases the H3K4me2/3 demethylation activity of KDM5B in cells by approximately 50% and increases the transcriptional repression of tumor suppressor genes by approximately twofold. These findings imply that PHD1KDM5B may help maintain KDM5B at target genes to mediate the demethylation activities of KDM5B.

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Sequence alignment of PHD fingers (binding to H3K4me3/2) of KDM5B (i.e., PHD3KDM5B), Lid (i.e., PHD3Lid), BPTF, ING2 and TAF3. The zinc-binding residues, H3A1-binding residues, H3R2-binding residues and H3K4me3/2-binding residues are highlighted in grey (and star on the top of KDM5B), blue, red and brown, respectively
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Fig5: Sequence alignment of PHD fingers (binding to H3K4me3/2) of KDM5B (i.e., PHD3KDM5B), Lid (i.e., PHD3Lid), BPTF, ING2 and TAF3. The zinc-binding residues, H3A1-binding residues, H3R2-binding residues and H3K4me3/2-binding residues are highlighted in grey (and star on the top of KDM5B), blue, red and brown, respectively

Mentions: Similar to PHD1KDM5B, PHD1Lid has also been suggested to interact with H3K4me0 (Li et al., 2010). PHD1Lid was proposed to bind to non-DNA elements, such as local chromatin environments, during H3K4me2/3 demethylation by Lid. The C-terminal PHD3 region of Lid (i.e., PHD3Lid) was observed to specifically bind to H3K4me2/3 through the interaction of aromatic residues in the PHD finger with the positively charged methylated H3K4. By aligning the amino acid sequences of PHD3KDM5B, PHD3Lid and other PHD fingers that recognize the H3K4me2/3 peptide (Fig. 5), we found that the residues most likely interacting with the H3K4me2/3 site are highly conserved. Residues W1781 in PHD3Lid and W1512 in PHD3KDM5B are conserved corresponding to W32 in PHDBPTF, W238 in PHDING2, and W891 in PHDTAF3. We thus suggested that PHD3KDM5B might also specifically bind to methylated H3K4me2/3 and that the W1502 residue in PHD3KDM5B may have a biological function similar to that of residues W1771 in PHD3Lid, Y17 in PHDBPTF, M226 in PHDING2 and M882 in PHDTAF3. In mammalian cells, c-Myc prefers to bind to E-boxes located within a chromatin context that contain highly di- and tri-methylated nucleosomal histone H3K4 (Guccione et al., 2006). However, the mechanism through which Myc recognizes the chromatin landscape remains unclear. Here, we propose that KDM5B may utilize its H3K4me2/3-binding C-terminal PHD3 finger to tether Myc to its preferred chromatin context. This process may be enhanced by the interaction between PHD1KDM5B and the unmethylated H3K4me0 N-terminal tail, thereby permitting the selection of biologically important E boxes. Further experiments are required to more precisely define the roles of KDM5B PHD fingers in cell growth.Figure 5


The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B.

Zhang Y, Yang H, Guo X, Rong N, Song Y, Xu Y, Lan W, Zhang X, Liu M, Xu Y, Cao C - Protein Cell (2014)

Sequence alignment of PHD fingers (binding to H3K4me3/2) of KDM5B (i.e., PHD3KDM5B), Lid (i.e., PHD3Lid), BPTF, ING2 and TAF3. The zinc-binding residues, H3A1-binding residues, H3R2-binding residues and H3K4me3/2-binding residues are highlighted in grey (and star on the top of KDM5B), blue, red and brown, respectively
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig5: Sequence alignment of PHD fingers (binding to H3K4me3/2) of KDM5B (i.e., PHD3KDM5B), Lid (i.e., PHD3Lid), BPTF, ING2 and TAF3. The zinc-binding residues, H3A1-binding residues, H3R2-binding residues and H3K4me3/2-binding residues are highlighted in grey (and star on the top of KDM5B), blue, red and brown, respectively
Mentions: Similar to PHD1KDM5B, PHD1Lid has also been suggested to interact with H3K4me0 (Li et al., 2010). PHD1Lid was proposed to bind to non-DNA elements, such as local chromatin environments, during H3K4me2/3 demethylation by Lid. The C-terminal PHD3 region of Lid (i.e., PHD3Lid) was observed to specifically bind to H3K4me2/3 through the interaction of aromatic residues in the PHD finger with the positively charged methylated H3K4. By aligning the amino acid sequences of PHD3KDM5B, PHD3Lid and other PHD fingers that recognize the H3K4me2/3 peptide (Fig. 5), we found that the residues most likely interacting with the H3K4me2/3 site are highly conserved. Residues W1781 in PHD3Lid and W1512 in PHD3KDM5B are conserved corresponding to W32 in PHDBPTF, W238 in PHDING2, and W891 in PHDTAF3. We thus suggested that PHD3KDM5B might also specifically bind to methylated H3K4me2/3 and that the W1502 residue in PHD3KDM5B may have a biological function similar to that of residues W1771 in PHD3Lid, Y17 in PHDBPTF, M226 in PHDING2 and M882 in PHDTAF3. In mammalian cells, c-Myc prefers to bind to E-boxes located within a chromatin context that contain highly di- and tri-methylated nucleosomal histone H3K4 (Guccione et al., 2006). However, the mechanism through which Myc recognizes the chromatin landscape remains unclear. Here, we propose that KDM5B may utilize its H3K4me2/3-binding C-terminal PHD3 finger to tether Myc to its preferred chromatin context. This process may be enhanced by the interaction between PHD1KDM5B and the unmethylated H3K4me0 N-terminal tail, thereby permitting the selection of biologically important E boxes. Further experiments are required to more precisely define the roles of KDM5B PHD fingers in cell growth.Figure 5

Bottom Line: KDM5B is a histone H3K4me2/3 demethylase.The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear.Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.

ABSTRACT
KDM5B is a histone H3K4me2/3 demethylase. The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear. In this paper, we observed that PHD1KDM5B interacts with unmethylated H3K4me0. Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers. The disruption of this interaction by double mutations on the residues in the interface (L325A/D328A) decreases the H3K4me2/3 demethylation activity of KDM5B in cells by approximately 50% and increases the transcriptional repression of tumor suppressor genes by approximately twofold. These findings imply that PHD1KDM5B may help maintain KDM5B at target genes to mediate the demethylation activities of KDM5B.

Show MeSH
Related in: MedlinePlus