Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromatin structure plays a crucial regulatory role in the control of gene expression. In eukaryotic nuclei, enzymatic complexes can alter this structure by both targeted covalent modification and ATP-dependent chromatin remodeling. Modification of histone amino termini by acetyltransferases and deacetylases correlates with transcriptional activation and repression [1-3], cell growth [4], and tumorigenesis [5]. Chromatin-remodeling enzymes of the Snf2 superfamily use ATP hydrolysis to restructure nucleosomes and chromatin, events which correlate with activation of transcription [6,7]. We purified a multi-subunit complex from Xenopus laevis eggs which contains six putative subunits including the known deacetylase subunits Rpd3 and RbAp48/p46 [8] as well as substoichiometric quantities of the deacetylase-associated protein Sin3 [9-13]. In addition, we identified one of the other components of the complex to be Mi-2, a Snf2 superfamily member previously identified as an autoantigen in the human connective tissue disease dermatomyositis [14,15]. We found that nucleosome-stimulated ATPase activity precisely copurified with both histone deacetylase activity and the deacetylase enzyme complex. This association of a histone deacetylase with a Snf2 superfamily ATPase suggests a functional link between these two disparate classes of chromatin regulators.
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PMID:A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. 966 95

The Ikaros gene family encodes zinc finger DNA-binding proteins essential for lineage determination and control of proliferation in the lymphoid system. Here, we report that, in the nucleus of a T cell, a major fraction of Ikaros and Aiolos proteins associate with the DNA-dependent ATPase Mi-2 and histone deacetylases, in a 2 MD complex. This Ikaros-NURD complex is active in chromatin remodeling and histone deacetylation. Upon T cell activation, Ikaros recruits Mi-2/HDAC to regions of heterochromatin. These studies reveal that Ikaros proteins are capable of targeting chromatin remodeling and deacetylation complexes in vivo. We propose that the restructuring of chromatin is a key aspect of Ikaros function in lymphocyte differentiation.
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PMID:Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. 1020 90

Methylation of DNA at the dinucleotide CpG is essential for mammalian development and is correlated with stable transcriptional silencing. This transcriptional silencing has recently been linked at a molecular level to histone deacetylation through the demonstration of a physical association between histone deacetylases and the methyl CpG-binding protein MeCP2 (refs 4,5). We previously purified a histone deacetylase complex from Xenopus laevis egg extracts that consists of six subunits, including an Rpd3-like deacetylase, the RbA p48/p46 histone-binding protein and the nucleosome-stimulated ATPase Mi-2 (ref. 6). Similar species were subsequently isolated from human cell lines, implying functional conservation across evolution. This complex represents the most abundant form of deacetylase in amphibian eggs and cultured mammalian cells. Here we identify the remaining three subunits of this enzyme complex. One of them binds specifically to methylated DNA in vitro and molecular cloning reveals a similarity to a known methyl CpG-binding protein. Our data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing.
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PMID:Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. 1047 84

The Mi-2 complex has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation. Here, we use a purified Mi-2 complex containing six components, Mi-2, Mta 1-like, p66, RbAp48, RPD3, and MBD3, to investigate the capacity of this complex to destabilize histone-DNA interactions and deacetylate core histones. The Mi-2 complex has ATPase activity that is stimulated by nucleosomes but not by free histones or DNA. This nucleosomal ATPase is relatively inefficient, yet is essential to facilitate both translational movement of histone octamers relative to DNA and the efficient deacetylation of the core histones within a mononucleosome. Surprisingly, ATPase activity had no effect on deacetylation of nucleosomal arrays.
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PMID:ATP-Dependent histone octamer mobilization and histone deacetylation mediated by the Mi-2 chromatin remodeling complex. 1081 92

Mi-2 and ISWI, two members of the Snf2 superfamily of ATPases, reside in separate ATP-dependent chromatin remodelling complexes. These complexes differ in their biochemical properties and are believed to perform distinct functions in the cell. We have compared the remodelling activity of recombinant Drosophila Mi-2 (dMi-2) with that of recombinant ISWI. Both proteins are nucleosome-stimulated ATPases and promote nucleosome mobilization. However, dMi-2 and ISWI differ in their interaction with nucleosome core particles, in their substrate requirements and in the direction of nucleosome mobilization. We have used antibodies to immobilize a complex containing dMi-2 and the dRPD3 histone deacetylase from Drosophila embryo extracts. This complex shares the nucleosome-stimulated ATPase and nucleosome mobilization properties of recombinant dMi-2, demonstrating that these activities are maintained in a physiological context. Its functional properties distinguish dMi-2 from both SWI2/SNF2 and ISWI, defining a new family of ATP-dependent remodelling machines.
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PMID:dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. 1094 16

Recent progress identifies targeted chromatin remodelling by co-repressor complexes as being an integral component of transcriptional silencing. Here we discuss how chromatin structure and the basal transcriptional machinery are manipulated by the co-repressor complex containing the Mi-2 nucleosomal ATPase, the histone-binding protein RbAp48 and histone deacetylase and by the co-repressor complex containing SIN3, RbAp48 and histone deacetylase. Remarkably, both of these complexes also contain methyl-CpG-binding proteins. This observation provides a molecular mechanism to integrate DNA methylation fully into gene control in vertebrates.
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PMID:Co-repressor complexes and remodelling chromatin for repression. 1096 24

We have previously described a SWI/SNF-related protein complex (PYR complex) that is restricted to definitive (adult-type) hematopoietic cells and that specifically binds DNA sequences containing long stretches of pyrimidines. Deletion of an intergenic DNA-binding site for this complex from a human beta-globin locus construct results in delayed human gamma- to beta-globin switching in transgenic mice, suggesting that the PYR complex acts to facilitate the switch. We now show that PYR complex DNA-binding activity also copurifies with subunits of a second type of chromatin-remodeling complex, nucleosome-remodeling deacetylase (NuRD), that has been shown to have both nucleosome-remodeling and histone deacetylase activities. Gel supershift assays using antibodies to the ATPase-helicase subunit of the NuRD complex, Mi-2 (CHD4), confirm that Mi-2 is a component of the PYR complex. In addition, we show that the hematopoietic cell-restricted zinc finger protein Ikaros copurifies with PYR complex DNA-binding activity and that antibodies to Ikaros also supershift the complex. We also show that NuRD and SWI/SNF components coimmunopurify with each other as well as with Ikaros. Competition gel shift experiments using partially purified PYR complex and recombinant Ikaros protein indicate that Ikaros functions as a DNA-binding subunit of the PYR complex. Our results suggest that Ikaros targets two types of chromatin-remodeling factors-activators (SWI/SNF) and repressors (NuRD)-in a single complex (PYR complex) to the beta-globin locus in adult erythroid cells. At the time of the switch from fetal to adult globin production, the PYR complex is assembled and may function to repress gamma-globin gene expression and facilitate gamma- to beta-globin switching.
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PMID:An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. 1100 53

ATP-dependent chromatin remodeling activities participate in the alteration of chromatin structure during gene regulation. All have DNA- or chromatin-stimulated ATPase activity and many can alter the structure of chromatin; however, the means by which they do this have remained unclear. Here we describe a novel activity for ATP-dependent chromatin remodeling activities, the ability to generate unconstrained negative superhelical torsion in DNA and chromatin. We find that the ability to distort DNA is shared by the yeast SWI/SNF complex, Xenopus Mi-2 complex, recombinant ISWI, and recombinant BRG1, suggesting that the generation of superhelical torsion represents a primary biomechanical activity shared by all Snf2p-related ATPase motors. The generation of superhelical torque provides a potent means by which ATP-dependent chromatin remodeling activities can manipulate chromatin structure.
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PMID:Generation of superhelical torsion by ATP-dependent chromatin remodeling activities. 1116 88

Drosophila Mi-2 (dMi-2) is the ATPase subunit of a complex combining ATP-dependent nucleosome remodelling and histone deacetylase activities. dMi-2 contains an HMG box-like region, two PHD fingers, two chromodomains and a SNF2-type ATPase domain. It is not known which of these domains contribute to nucleosome remodelling. We have tested a panel of dMi-2 deletion mutants in ATPase, nucleosome mobilization and nucleosome binding assays. Deletion of the chromodomains impairs all three activities. A dMi-2 mutant lacking the chromodomains is incorporated into a functional histone deacetylase complex in vivo but has lost nucleosome-stimulated ATPase activity. In contrast to dHP1, dMi-2 does not bind methylated histone H3 tails and does not require histone tails for nucleosome binding. Instead, the dMi-2 chromodomains display DNA binding activity that is not shared by other chromodomains. Our results suggest that the chromodomains act at an early step of the remodelling process to bind the nucleosome substrate predominantly via protein-DNA interactions. Furthermore, we identify DNA binding as a novel chromodomain-associated activity.
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PMID:The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization. 1200 95

Mammalian Mi-2, an auto-antigen for dermatomyositis, is known to be an adenosine triphosphate (ATP)-dependent nucleosome remodelling factor. The Drosophila homologue of Mi-2 (dMi-2) gene is located at 76D5-6 on the left arm of the third chromosome and is transcribed into two alternate transcripts (dMi-2a and dMi-2b). Both transcripts are present at high levels in the ovary and during the first 8 h of embryogenesis when detected by Northern blot analysis. The localization of protein was nuclear, which is consistent with its proposed function as a component of the chromatin remodelling complex. Several lines of recessive mutants including mutations in dMi-2 were isolated and classified into four different complementation groups. Four alleles of dMi-2 mutants were further characterized in molecular nature; dMi-2(BL1) was found to have a mutation in the ATP-binding motif of the ATPase domain, dMi-2(BL7) in the core histidine of the first plant homeodomain zinc finger and dMi-2(BL12) in a conserved serine in the chromodomain. On the other hand, dMi-2(BL3) did not have any change in the coding region. The expression pattern of dMi-2 and the embryonic lethal phenotypes of mutants indicate that dMi-2 is essential for embryonic development in Drosophila melanagaster.
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PMID:Genetic characterization of Drosophila Mi-2 ATPase. 1213 48


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