scholarly journals Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 773
Author(s):  
Purna Chaitanya Konduri ◽  
Tianyuan Wang ◽  
Narges Salamat ◽  
Li Zhang
Keyword(s):  
Histone Demethylase ◽  
Interacting Proteins ◽  
Cellular Functions ◽  
Functional Activities ◽  
Nutritional Conditions ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Metabolic Sensor ◽  
Heme Regulation ◽  
Partner Proteins

The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.

JmjN interacts with JmjC to ensure selective proteolysis of Gis1 by the proteasome

Microbiology ◽  
2011 ◽  
Vol 157 (9) ◽  
pp. 2694-2701 ◽  
Author(s):  
Zhenzhen Quan ◽  
Stephen G. Oliver ◽  
Nianshu Zhang
Keyword(s):  
Structural Unit ◽  
Transcription Activation ◽  
Histone Demethylase ◽  
Transcription Activity ◽  
The Core ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Β Sheets ◽  
The Stability ◽  
Selective Proteolysis

A group of JmjC domain-containing proteins also harbour JmjN domains. Although the JmjC domain is known to possess histone demethylase activity, the function of the JmjN domain remains largely undetermined. Previously, we have demonstrated that the yeast Gis1 transcription factor, bearing both JmjN and JmjC domains at its N terminus, is subject to proteasome-mediated selective proteolysis to downregulate its transcription activation ability. Here, we reveal that the JmjN and JmjC domains interact with each other through two β-sheets, one in each domain. Removal of either or both β-strands or the entire JmjN domain leads to complete degradation of Gis1, mediated partially by the proteasome. Mutating the core residues essential for histone demethylase activity demonstrated for other JmjC-containing proteins or deleting both Jumonji domains enhances the transcription activity of Gis1, but has no impact on its selective proteolysis by the proteasome. Together, these data suggest that JmjN and JmjC interact physically to form a structural unit that ensures the stability and appropriate transcription activity of Gis1.

Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism

2010 ◽  
Vol 433 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Yuanyuan Chang ◽  
Jian Wu ◽  
Xia-Jing Tong ◽  
Jin-Qiu Zhou ◽  
Jianping Ding
Keyword(s):  
Substrate Specificity ◽  
Substrate Binding ◽  
Histone Demethylase ◽  
Structural Motif ◽  
Catalytic Core ◽  
Conserved Residues ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Saccharomyces Cerevesiae ◽  
Binding Cleft

Saccharomyces cerevesiae Rph1 is a histone demethylase orthologous to human JMJD2A (Jumonji-domain-containing protein 2A) that can specifically demethylate tri- and di-methylated Lys36 of histone H3. c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes. In the present work, we report the crystal structures of c-Rph1 in apo form and in complex with Ni2+ and α-KG [2-oxoglutarate (α-ketoglutarate)]. The structure of c-Rph1 is composed of a JmjN (Jumonji N) domain, a long β-hairpin, a mixed structural motif and a JmjC domain. The α-KG cofactor forms hydrogen-bonding interactions with the side chains of conserved residues, and the Ni2+ ion at the active site is chelated by conserved residues and the cofactor. Structural comparison of Rph1 with JMJD2A indicates that the substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long β-hairpin and the mixed structural motif; and the methylated Lys36 of H3 is recognized by several conserved residues of the JmjC domain. In vitro biochemical results show that mutations of the key residues at the catalytic centre and in the substrate-binding cleft abolish the demethylase activity. In vivo growth phenotype analyses also demonstrate that these residues are essential for its functional roles in transcription elongation. Taken together, our structural and biological data provide insights into the molecular basis of the histone demethylase activity and the substrate specificity of Rph1.

scholarly journals Noncatalytic Function of a JmjC Domain Protein Disrupts Heterochromatin

2019 ◽  
Vol 12 ◽  
pp. 251686571986224
Author(s):  
Kehan Bao ◽  
Songtao Jia
Keyword(s):  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Histone Acetyltransferase ◽  
Histone Demethylase ◽  
Epigenetic Landscape ◽  
Disease Etiology ◽  
Chromatin Regulators ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Domain Protein

Chromatin-modifying enzymes are frequently overexpressed in cancer cells, and their enzymatic activities play important roles in changing the epigenetic landscape responsible for tumorigenesis. However, many of these proteins also execute noncatalytic functions, which are poorly understood. In fission yeast, overexpression of Epe1, a histone demethylase homolog, causes heterochromatin defects. Interestingly, in our recent work, we discovered that overexpressed Epe1 recruits SAGA, a histone acetyltransferase complex important for transcriptional regulation, to disrupt heterochromatin, independent of its demethylase activity. Our findings suggest that overexpressed chromatin-modifying enzymes can alter the epigenetic landscape through changing their proteomic environments, an area that needs to be further explored in dissecting disease etiology associated with overexpression of chromatin regulators.

Structure of the JmjC-domain-containing protein JMJD5

2013 ◽  
Vol 69 (10) ◽  
pp. 1911-1920 ◽  
Author(s):  
Haipeng Wang ◽  
Xing Zhou ◽  
Minhao Wu ◽  
Chengliang Wang ◽  
Xiaoqin Zhang ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Embryonic Cell ◽  
Histone Demethylase ◽  
Amino Acid Residues ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Active Centre ◽  
Histone Tails ◽  
Demethylase Activity ◽  
Jmjc Domain

The post-translational modification of histone tails is the principal process controlling epigenetic regulation in eukaryotes. The lysine methylation of histones is dynamically regulated by two distinct classes of enzymes: methyltransferases and demethylases. JMJD5, which plays an important role in cell-cycle progression, circadian rhythms and embryonic cell proliferation, has been shown to be a JmjC-domain-containing histone demethylase with enzymatic activity towards H3K36me2. Here, the crystal structure of human JMJD5 lacking the N-terminal 175 amino-acid residues is reported. The structure showed that the Gln275, Trp310 and Trp414 side chains might block the insertion of methylated lysine into the active centre of JMJD5, suppressing the histone demethylase activity of the truncated JMJD5 construct. A comparison of the structure of JMJD5 with that of FIH, a well characterized protein hydroxylase, revealed that human JMJD5 might function as a protein hydroxylase. The interaction between JMJD5 and the core histone octamer proteins indicated that the histone proteins could be potential substrates for JMJD5.

scholarly journals Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhiqiang Du ◽  
Jeniece Regan ◽  
Elizabeth Bartom ◽  
Wei-Sheng Wu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Regulation Of Transcription ◽  
Interacting Proteins ◽  
Environmental Stress Response ◽  
Key Factors ◽  
Cellular Functions ◽  
Beneficial Effects ◽  
Genome Wide ◽  
Genes Encoding ◽  
A Subunit

AbstractTranscriptional regulators are prevalent among identified prions in Saccharomyces cerevisiae, however, it is unclear how prions affect genome-wide transcription. We show here that the prion ([SWI+]) and mutant (swi1∆) forms of Swi1, a subunit of the SWI/SNF chromatin-remodeling complex, confer dramatically distinct transcriptomic profiles. In [SWI+] cells, genes encoding for 34 transcription factors (TFs) and 24 Swi1-interacting proteins can undergo transcriptional modifications. Several TFs show enhanced aggregation in [SWI+] cells. Further analyses suggest that such alterations are key factors in specifying the transcriptomic signatures of [SWI+] cells. Interestingly, swi1∆ and [SWI+] impose distinct and oftentimes opposite effects on cellular functions. Translation-associated activities, in particular, are significantly reduced in swi1∆ cells. Although both swi1∆ and [SWI+] cells are similarly sensitive to thermal, osmotic and drought stresses, harmful, neutral or beneficial effects were observed for a panel of tested chemical stressors. Further analyses suggest that the environmental stress response (ESR) is mechanistically different between swi1∆ and [SWI+] cells—stress-inducible ESR (iESR) are repressed by [SWI+] but unchanged by swi1∆ while stress-repressible ESR (rESR) are induced by [SWI+] but repressed by swi1∆. Our work thus demonstrates primarily gain-of-function outcomes through transcriptomic modifications by [SWI+] and highlights a prion-mediated regulation of transcription and phenotypes in yeast.

scholarly journals Detection of secondary binding sites in proteins using fragment screening

2015 ◽  
Vol 112 (52) ◽  
pp. 15910-15915 ◽  
Author(s):  
R. Frederick Ludlow ◽  
Marcel L. Verdonk ◽  
Harpreet K. Saini ◽  
Ian J. Tickle ◽  
Harren Jhoti
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Cellular Functions ◽  
Modulate Function ◽  
Protein Targets ◽  
Biologically Relevant ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
High Conservation ◽  
Partner Proteins

Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.

scholarly journals Characterization and Stress Response of the JmjC Domain-Containing Histone Demethylase Gene Family in the Allotetraploid Cotton Species Gossypium hirsutum

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1617
Author(s):  
Jie Zhang ◽  
Junping Feng ◽  
Wei Liu ◽  
Zhongying Ren ◽  
Junjie Zhao ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Stress Response ◽  
Gossypium Hirsutum ◽  
Gene Family ◽  
Function Analysis ◽  
Histone Demethylase ◽  
Abiotic Stress Response ◽  
Cotton Species ◽  
Jmjc Domain ◽  
Allotetraploid Cotton

Histone modification is an important epigenetic modification that controls gene transcriptional regulation in eukaryotes. Histone methylation is accomplished by histone methyltransferase and can occur on two amino acid residues, arginine and lysine. JumonjiC (JmjC) domain-containing histone demethylase regulates gene transcription and chromatin structure by changing the methylation state of the lysine residue site and plays an important role in plant growth and development. In this study, we carried out genome-wide identification and comprehensive analysis of JmjC genes in the allotetraploid cotton species Gossypium hirsutum. In total, 50 JmjC genes were identified and in G. hirsutum, and 25 JmjC genes were identified in its two diploid progenitors, G. arboreum and G. raimondii, respectively. Phylogenetic analysis divided these JmjC genes into five subfamilies. A collinearity analysis of the two subgenomes of G. hirsutum and the genomes of G. arboreum and G. raimondii uncovered a one-to-one relationship between homologous genes of the JmjC gene family. Most homologs in the JmjC gene family between A and D subgenomes of G. hirsutum have similar exon-intron structures, which indicated that JmjC family genes were conserved after the polyploidization. All G. hirsutumJmjC genes were found to have a typical JmjC domain, and some genes also possess other special domains important for their function. Analysis of promoter regions revealed that cis-acting elements, such as those related to hormone and abiotic stress response, were enriched in G. hirsutum JmjC genes. According to a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, most G. hirsutumJmjC genes had high abundance expression at developmental stages of fibers, suggesting that they might participate in cotton fiber development. In addition, some G. hirsutumJmjC genes were found to have different degrees of response to cold or osmotic stress, thus indicating their potential role in these types of abiotic stress response. Our results provide useful information for understanding the evolutionary history and biological function of JmjC genes in cotton.

scholarly journals KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Cancer Cell ◽  
2019 ◽  
Vol 35 (2) ◽  
pp. 330-332 ◽  
Author(s):  
Kunihiko Hinohara ◽  
Hua-Jun Wu ◽  
Sébastien Vigneau ◽  
Thomas O. McDonald ◽  
Kyomi J. Igarashi ◽  
...  
Keyword(s):  
Histone Demethylase ◽  
Therapeutic Resistance ◽  
Demethylase Activity

scholarly journals A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Lei Wang ◽  
Jianjun Chang ◽  
Diana Varghese ◽  
Michael Dellinger ◽  
Subodh Kumar ◽  
...  
Keyword(s):  
Small Molecule ◽  
Histone Demethylase ◽  
Cancer Growth ◽  
Demethylase Activity
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