Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling

Longbotham, James E.; Chio, Cynthia M.; Dharmarajan, Venkatasubramanian; Trnka, Michael J.; Torres, Idelisse Ortiz; Goswami, Devrishi; Ruiz, Karen; Burlingame, Alma L.; Griffin, Patrick R.; Fujimori, Danica Galonić

doi:10.1038/s41467-018-07829-z

Cited by 41 publications

(71 citation statements)

References 69 publications

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“…The observed difference in K M app also explains the preference of KDM5 enzymes toward longer peptide substrates. 3,4 Acetylation of K14 and K18 is associated with active transcription, and a previous study identified a positive crosstalk between these modifications and K4me3. 8 Hence, we proceeded to test how acetylation of K14 (K14ac) and K18 (K18ac) affects KDM5A substrate engagement and activity.…”

Section: Kdm5a Recognizes An H3 Epitope Distal To K4mentioning

confidence: 92%

“…5 While PHD1 is required for efficient demethylation in cells, the deletion of the PHD2 and PHD3 domains does not abrogate demethylase activity, and a KDM5A construct that lacks these domains (KDM5A 1-797 ) has been utilized for the in vitro characterization of this protein (Figure 1b). 3,4,6,7 The presence of multiple methylated lysine residues in the H3 tail ( Figure 1c) raises questions about the molecular basis for H3K4-specific demethylation by KDM5A. [8][9][10][11] Currently, there is limited information regarding the molecular details of KDM5A substrate recognition.…”

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confidence: 99%

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Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A

2020

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Human lysine demethylase KDM5A is a chromatin-modifying enzyme associated with transcriptional regulation, because of its ability to catalyze removal of methyl groups from methylated lysine 4 of histone H3 (H3K4me3). Amplification of KDM5A is observed in many cancers, including breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer, and gastric cancer. In this study, we employed alanine scanning mutagenesis to investigate substrate recognition of KDM5A and identify the H3 tail residues necessary for KDM5A-catalyzed demethylation. Our data show that the H3Q5 residue is critical for substrate recognition by KDM5A. Our data also reveal that the protein-protein interactions between KDM5A and the histone H3 tail extend beyond the amino acids proximal to the substrate mark. Specifically, demethylation activity assays show that deletion or mutation of residues at positions 14-18 on the H3 tail results in an 8-fold increase in the K M app , compared to wild-type 18mer peptide, suggesting that this distal epitope is important in histone engagement. Finally, we demonstrate that posttranslational modifications on this distal epitope can modulate KDM5A-dependent demethylation. Our findings provide insights into H3K4-specific recognition by KDM5A, as well as how chromatin context can regulate KDM5A activity and H3K4 methylation status.

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Section: Kdm5a Recognizes An H3 Epitope Distal To K4mentioning

confidence: 92%

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confidence: 99%

Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A

2020

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“…3 E, right) [ 131 ]. Interestingly, the PHD1 domains of KDM5A and KDM5B have been shown to allosterically activate these enzymes upon binding their own product, H3K4me0 [ [132] , [133] , [134] ]. This positive feedback mechanism may drive propagation of demethylation along nucleosomes to remove large H3K4me3 domains upon switching to a transcriptionally inactive state, or serve to maintain methylation-free chromatin domains [ 131 , 135 ].…”

Section: Regulating H3k4me3 At Cpg Island-associated Gene Promotersmentioning

confidence: 99%

Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation

Hughes

Kelley

Klose

2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

104

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The precise regulation of gene transcription is required to establish and maintain cell type-specific gene expression programs during multicellular development. In addition to transcription factors, chromatin, and its chemical modification, play a central role in regulating gene expression. In vertebrates, DNA is pervasively methylated at CG dinucleotides, a modification that is repressive to transcription. However, approximately 70% of vertebrate gene promoters are associated with DNA elements called CpG islands (CGIs) that are refractory to DNA methylation. CGIs integrate the activity of a range of chromatin-regulating factors that can post-translationally modify histones and modulate gene expression. This is exemplified by the trimethylation of histone H3 at lysine 4 (H3K4me3), which is enriched at CGI-associated gene promoters and correlates with transcriptional activity. Through studying H3K4me3 at CGIs it has become clear that CGIs shape the distribution of H3K4me3 and, in turn, H3K4me3 influences the chromatin landscape at CGIs. Here we will discuss our understanding of the emerging relationship between CGIs, H3K4me3, and gene expression.

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“…PHD3 is also known to form a fusion with NUP98 in acute leukemia 16 . We have previously shown that the PHD1 domain preferentially binds unmodified H3 42 and that the engagement of the PHD1 domain with its ligand allosterically enhances the demethylation activity of KDM5A by stabilizing substrate binding to the catalytic domain 43 . Despite the importance of PHD1 in the demethylase activity of KDM5A, there is limited structural information on how its PHD1 domain interacts with H3 and how it can discriminate against the methylation states of H3K4 peptides.…”

Section: Introductionmentioning

confidence: 99%

Recognition of histone H3 methylation states by the PHD1 domain of histone demethylase KDM5A

Longbotham

Fujimori

2019

Preprint

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PHD reader domains are chromatin binding modules often responsible for the recruitment of large protein complexes that contain histone modifying enzymes, chromatin remodelers and DNA repair machinery. PHD domains recognize N-terminal residues of histone H3 and are sensitive to the methylation state of Lys4 in histone H3 (H3K4). Histone demethylase KDM5A, an epigenetic eraser enzyme that contains three PHD domains, is often overexpressed in various cancers and its demethylation activity is allosterically enhanced when its PHD1 domain is bound to the H3 tail. The allosteric regulatory function of PHD1 expands roles of reader domains, suggesting unique features of this chromatin interacting module. Our previous studies determined the H3 binding site of PHD1, although it remains unclear how the H3 tail interacts with the N-terminal residues of PHD1 and how PHD1 discriminates against H3 tails with varying degrees of H3K4 methylation. Here we show that the N-terminal region of PHD1 is initially unstructured, but becomes ordered upon binding of the high affinity H3 peptide ligands. We also observe differential interactions of conserved binding residues with differently methylated H3K4 peptides (me0, me1, me2 or me3), providing a rational for this PHD1 domain's preference for lower methylation states of H3K4.We further assessed the contributions of various H3 interacting residues in the PHD1 domain to the binding of H3 peptides using mutagenesis. The insights into the H3 binding site could provide useful information to aid development of allosteric small molecule modulators of KDM5A.

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Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling

Cited by 41 publications

References 69 publications

Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A

Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A

Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation

Recognition of histone H3 methylation states by the PHD1 domain of histone demethylase KDM5A

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