共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
The study of histone lysine demethylases has become very hot recently. Many histone demethylases have been reported by different research groups with various techniques. However, how many histone lysine-methylation states can be removed by one specific demethylase and how many demethylases can remove one specific histone lysine-methylation state? It remains a daunting challenge to answer these questions to date. An in-depth discussion on recent results, three important points were provided: (1) Some demethylases can remove more histone lysine-methylation states; (2) Some prokaryotes might be endowed with histone lysine demethylases although they are devoid of histones; (3) Protein-protein interaction provides a valuable framework for a better understanding of the functions of the histone lysine demethylases. All of these will be beneficial to a better understanding of demethylases and suggest how future research can be improved. 相似文献
3.
4.
5.
6.
V.K. Chaithanya Ponnaluri 《Biochemical and biophysical research communications》2009,390(2):280-41625
7.
Structural insights into histone demethylation by JMJD2 family members 总被引:24,自引:0,他引:24
Chen Z Zang J Whetstine J Hong X Davrazou F Kutateladze TG Simpson M Mao Q Pan CH Dai S Hagman J Hansen K Shi Y Zhang G 《Cell》2006,125(4):691-702
8.
Couture JF Collazo E Ortiz-Tello PA Brunzelle JS Trievel RC 《Nature structural & molecular biology》2007,14(8):689-695
JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs. 相似文献
9.
10.
Gray SG Iglesias AH Lizcano F Villanueva R Camelo S Jingu H Teh BT Koibuchi N Chin WW Kokkotou E Dangond F 《The Journal of biological chemistry》2005,280(31):28507-28518
To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G(2)/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis. 相似文献
11.
12.
Histone modifications have great importance in epigenetic regulation. JMJD2A is a histone demethylase which is selective for di- and trimethyl forms of residues Lys9 and Lys36 of Histone 3 tail (H3K9 and H3K36). We present a molecular dynamics simulations of mono-, di- and trimethylated histone tails in complex with JMJD2A catalytic domain to gain insight into how JMJD2A discriminates between the methylation states of H3K9. The methyl groups are located at specific distances and orientations with respect to Fe(II) in methylammonium binding pocket. For the trimethyllysine the mechanism which provides the effectual orientation of methyl groups is the symmetry, whereas for the dimethyllysine case the determining factors are the interactions between methyllysine head and its environment and subsequently the restriction on angular motion. The occurrence frequency of methyl groups in a certain proximity of Fe(II) comes out as the explanation of the enzyme activity difference on di- and tri-methylated peptides. Energy analysis suggests that recognition is mostly driven by van der Waals and followed by Coulombic interactions in the enzyme-substrate interface. The number (mono, di or tri) and orientations of methyl groups and water molecules significantly affect the extent of van der Waals interaction strengths. Hydrogen bonding analysis suggests that the interaction between JMJD2A and its substrates mainly comes from main chain-side chain interactions. Binding free energy analysis points out Arg8 as an important residue forming an intra-substrate hydrogen bond with tri and dimethylated Lys9 of the H3 chain. Our study provides new insights into how JMJD2A discriminates between its substrates from both a structural and dynamical point of view. 相似文献
13.
Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases 总被引:34,自引:0,他引:34
Whetstine JR Nottke A Lan F Huarte M Smolikov S Chen Z Spooner E Li E Zhang G Colaiacovo M Shi Y 《Cell》2006,125(3):467-481
14.
Coralie Poulard Juliette Rambaud Emilie Lavergne Julien Jacquemetton Jack-Michel Renoir Olivier Trédan Sylvie Chabaud Isabelle Treilleux Laura Corbo Muriel Le Romancer 《PloS one》2015,10(5)
BackgroundProtein arginine methylation is a common post translational modification that regulates protein properties. This modification is carried out by a family of nine arginine methyltransferases (PRMTs). Arginine methylation has already been linked to tumourigenesis as overexpression of these enzymes was associated with various cancers, notably in breast cancers. Since the Jumonji Domain Containing 6 protein (JMJD6) possesses an arginine demethylase activity able to remove the methyl mark, we wanted to assess its potential role in breast tumourigenesis.MethodsThe expression of the protein by tissue microarray immunohistochemical staining was performed on a cohort of 133 breast tumours. Using cell lines stably overexpressing or knocked down for JMJD6, we evaluated its role on cell proliferation, cell migration, colony formation and mice tumour xenografts.ResultsThe analysis of JMJD6 expression in a cohort of breast tumour samples indicates that JMJD6 was highly expressed in aggressive breast tumours. Moreover, high expression of JMJD6 was associated with poor disease-free survival of patients in this cohort. JMJD6 silencing in breast tumoural cells promotes certain characteristics of tumourigenesis including proliferation, migration in vitro, and tumour growth in vivo. These effects are dependent on its demethylase activity as an enzymatic dead mutant lost these properties.ConclusionsAlthough JMJD6 displays anti-tumoral properties in cell lines, its expression in breast tumours may be a marker of poor prognosis, suggesting that its function could be altered in breast cancer. 相似文献
15.
16.
17.
18.
19.
U Leurs RP Clausen JL Kristensen B Lohse 《Bioorganic & medicinal chemistry letters》2012,22(18):5811-5813
The human histone demethylases of the KDM4 (JMJD2) family have been associated to diseases such as prostate and breast cancer, as well as X-linked mental retardation. Therefore, these enzymes are considered oncogenes and their selective inhibition might be a possible therapeutic approach to treat cancer. Here we describe a heterocyclic ring system library screened against the histone demethylase KDM4C (JMJD2C) in the search for novel inhibitory scaffolds. A 4-hydroxypyrazole scaffold was identified as an inhibitor of KDM4C; this scaffold could be employed in the further development of novel therapeutics, as well as for the elucidation of the biological roles of KDM4C on epigenetic regulation. 相似文献
20.
In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyllysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review. 相似文献