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)

In eukaryotes, ORC (origin recognition complex), a six-protein complex, is the most likely initiator of chromosomal DNA replication. ORC belongs to the AAA(+) (ATPases associated with a variety of cellular activities) family of proteins and has intrinsic ATPase activity derived from Orc1p, one of its subunits. To reveal the role of this ATPase activity in Saccharomyces cerevisiae (baker's yeast) ORC, we mutated the Orc1p sensor 1 and sensor 2 regions, which are important for ATPase activity in AAA(+) proteins. Plasmid-shuffling analysis revealed that Asn(600), Arg(694) and Arg(704) are essential for the function of Orc1p. In yeast cells, overexpression of Orc1R694Ep inhibited growth, caused inefficient loading of MCM (mini-chromosome maintenance complex of proteins) and slowed the progression of S phase. In vitro, purified ORC-1R [ORC with Orc1R694Ep (Orc1p Arg(694)-->Glu mutant)] has decreased ATPase activity in the presence or absence of origin DNA. However, other activities (ATP binding and origin DNA binding) were indistinguishable from those of wild-type ORC. The present study showed that Arg(694) of the Orc1p subunit is important for the ATPase activity of ORC and suggests that this ATPase activity is required for efficient MCM loading on to origin DNA and for progression of S phase.
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PMID:Analysis of mutant origin recognition complex with reduced ATPase activity in vivo and in vitro. 1839 42

The human sarco/endoplasmic reticulum (ER) Ca(2+)ATPase 3 (SERCA3) gene gives rise to SERCA3a-3f isoforms, the latter inducing ER stress in vitro. Here, we first demonstrated the co-expression of SERCA3a, -3d and -3f proteins in the heart. Evidence for endogenous proteins was obtained by using isoform-specific antibodies including a new SERCA3d-specific antibody, and either Western blotting of protein lysates or immunoprecipitation of membrane proteins. An immunolocalization study of both left ventricle tissue and isolated cardiomyocytes showed a distinct compartmentalization of the SERCA3 isoforms, as a uniform distribution of SERCA3a was detected while -3d and -3f isoforms were observed around the nucleus and in close vicinity of plasma membrane, respectively. Second, we studied their expressions in failing hearts including mixed (MCM) (n=1) and idiopathic dilated (IDCM) cardiomyopathies (n=4). Compared with controls (n=5), similar expressions of SERCA3a and -3d mRNAs were observed in all patients. In contrast, SERCA3f mRNA was found to be up-regulated in failing hearts (125+/-7%). Remarkably, overexpression of SERCA3f paralleled an increase in ER stress markers including processing of X-box-binding protein-1 (XBP-1) mRNA (176+/-24%), and expression of XBP-1 protein and glucose-regulated protein (GRP)78 (232+/-21%). These findings revisit the human heart's Ca(2+)ATPase system and indicate that SERCA3f may account for the mechanism of ER stress in vivo in heart failure.
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PMID:Compartmentalized expression of three novel sarco/endoplasmic reticulum Ca2+ATPase 3 isoforms including the switch to ER stress, SERCA3f, in non-failing and failing human heart. 1894 68

In eukaryotic cells, MCM, the minichromosome maintenance proteins, form a heterohexamer during G(1) phase in the cell cycle and constitute a DNA helicase activity at the onset of replication. MCM proteins are downregulated and dissociated from chromatin when cells exit the cell cycle. MCM proteins are upregulated frequently in a variety of dysplastic and cancer cells. To delineate the role of MCM in esophageal epithelial biology, we determined the MCM family gene expression during cellular senescence, immortalization, differentiation and apoptosis. All of the MCM2-7 proteins appeared to be downregulated in primary human esophageal keratinocytes upon replicative senescence. Their expression was restored by ectopic expression of a catalytic subunit of human telomerase, resulting in immortalization. Interestingly, we found a reciprocal induction of a novel MCM2-related protein fragment upon cell growth inhibition associated with senescence, contact inhibition or terminal differentiation, but not apoptosis. Epitope mapping of this MCM2-related fragment suggested the lack of amino- and carboxyl-terminal regions, including one of the putative nuclear localization signals and the ATPase domain, the MCM box. The absence of multiple MCM2 transcripts implied a possible posttranslational molecular cleavage in generation of the MCM2-related fragment, and a potential functional role in the regulation of the activity of the MCM protein complex.
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PMID:Cleavage of MCM2 licensing protein fosters senescence in human keratinocytes. 1900 46

There are a large number of proteins involved in the control of eukaryotic DNA replication, which act together to ensure DNA is replicated only once every cell cycle. Key proteins involved in the initiation and elongation phases of DNA replication include the MCM (minchromosome maintenance) proteins, MCM2-MCM7, a family of six related proteins believed to act as the replicative helicase. Genome sequencing has revealed that the archaea possess a simplified set of eukaryotic replication homologues. The complexity of the DNA replication machinery in eukaryotes has led to a number of archaeal species being adapted as model organisms for the study of the DNA replication process. Most archaea sequenced to date possess a single MCM homologue that forms a hexameric complex. Recombinant MCMs from several archaea have been used in the biochemical characterization of the protein, revealing that the MCM complex has ATPase, DNA-binding and -unwinding activities. Unusually, the genome of the methanogenic archaeon Methanococcus maripaludis contains four MCM homologues, all of which contain the conserved motifs required for function. The availability of a wide range of genetic tools for the manipulation of M. maripaludis and the relative ease of growth of this organism in the laboratory makes it a good potential model for studying the role of multiple MCMs in DNA replication.
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PMID:Methanococcus maripaludis: an archaeon with multiple functional MCM proteins? 1914 92

Recent work has identified a "glutamate switch" in six of the seven clades of AAA+ ATPases. The glutamate switch acts to transduce information regarding substrate binding to the ATPase active site. We provide biochemical evidence that a highly conserved threonine residue acts as a glutamate switch in the replicative helicase, MCM, and, thus, reveal that the glutamate switch is a feature common to all seven AAA+ clades.
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PMID:The glutamate switch is present in all seven clades of AAA+ protein. 1970 28

The initiation of DNA replication starts from origins and is controlled by a multiprotein complex, which involves about twenty protein factors. One of the important factors is hetrohexameric minichromosome maintenance (MCM2-7) protein complex which is evolutionary conserved and functions as essential replicative helicase for DNA replication. Here we report the isolation and characterization of a single subunit of pea MCM protein complex, the MCM6. The deduced amino acid (827) sequence contains all the known canonical MCM motifs including zinc finger, MCM specific Walker A and Walker B and arginine finger. The purified recombinant protein contains ATP-dependent 3'-5' DNA helicase, ATP-binding and ATPase activities. The helicase activity was stimulated by replication fork like substrate and anti-MCM6 antibodies curtail all the enzyme activities of MCM6 protein. In vitro it self-interacts and forms a homohexamer which is active for DNA helicase and ATPase activities. The complete protein is required for self-interaction as the truncated MCM6 proteins were unable to self-interact. Western blot analysis and in vivo immunostaining followed by confocal microscopy showed the localization of MCM6 both in the nucleus and cytosol. These findings provide first direct evidence that single subunit MCM6 contains DNA helicase activity which is unique to plant MCM6 protein, as this activity was only reported for heteromultimers of MCM proteins in animal system. This discovery should make an important contribution to a better understanding of DNA replication in plants.
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PMID:A single subunit MCM6 from pea forms homohexamer and functions as DNA helicase. 2073 May 96

The MCM (minichromosome maintenance protein) protein family was identified for the first time in budding yeast, Saccharomyces cerevisiae. The subgroup consists of MCM proteins 2-9, that possess the characteristic ATPase domain (MCM box). There are also MCM1 and MCM10, which are important in DNA replication, but they do not possess the specific MCM box. The main function of MCM proteins is cooperation with other factors in molecular mechanisms that form the replication fork and in regulation of DNA synthesis. MCM proteins form a ring-shaped complex, which is activated when other factors are bound. MCM 2-7 complex is one of the pre-replication factors. Association of MCM 2-7 complex is a crucial moment initiating the replication fork. MCM proteins play a role in maintaining genome integrity and prevent re-replication once per cell cycle. Proliferating cells have high levels of MCM, whereas they are not detected in quiescent, differentiated or senescent cells. They are also potential useful markers of cell proliferation. Recent studies suggested that MCMs are good markers of proliferation activity degree, because they are highly expressed in a variety of tumors. The aim of this work is to summarize current knowledge about the role of MCM proteins in DNA replication and potential diagnostic markers of proliferating cancer cells.
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PMID:[The role of MCM proteins in cell proliferation and tumorigenesis]. 2116 97

The MCM (minichromosome maintenance) proteins of archaea are widely believed to be the replicative DNA helicase of these organisms. Most archaea possess a single MCM orthologue that forms homo-multimeric assemblies with a single hexamer believed to be the active form. In the present study we characterize the roles of highly conserved residues in the ATPase domain of the MCM of the hyperthermophilic archaeon Sulfolobus solfataricus. Our results identify a potential conduit for communicating DNA-binding information to the ATPase active site.
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PMID:The interplay of DNA binding, ATP hydrolysis and helicase activities of the archaeal MCM helicase. 2136 71

In eukaryotes, the replicative DNA helicase 'core' is the minichromosome maintenance (Mcm) complex (MCM), forming a heterohexameric complex consisting of six subunits (Mcm2-7). Recent studies showed that the CMG (Cdc45-MCM-GINS) complex is the actual helicase body in the replication fork progression complex. In Archaea, Thermococcus kodakarensis harbors three genes encoding the Mcm homologs on its genome, contrary to most archaea, which have only one homolog. It is thus, of high interest, whether and how these three Mcms share their functions in DNA metabolism in this hyperthermophile. Here, we report the biochemical properties of two of these proteins, TkoMcm1 and TkoMcm3. In addition, their physical and functional interactions with GINS, possibly an essential factor for the initiation and elongation process of DNA replication, are presented through in vitro ATPase and helicase assays, and an in vivo immunoprecipitation assay. Gene disruption and product quantification analyses suggested that TkoMcm3 is essential for cell growth and plays a key role as the main DNA helicase in DNA replication, whereas TkoMcm1 also shares some function in the cells.
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PMID:Biochemical and genetical analyses of the three mcm genes from the hyperthermophilic archaeon, Thermococcus kodakarensis. 2209 66

In a previous Research article (Froelich et al., 2014), we suggested an MCM helicase activation mechanism, but were limited in discussing the ATPase domain because it was absent from the crystal structure. Here we present the crystal structure of a nearly full-length MCM hexamer that is helicase-active and thus has all features essential for unwinding DNA. The structure is a chimera of Sulfolobus solfataricus N-terminal domain and Pyrococcus furiosus ATPase domain. We discuss three major findings: 1) a novel conformation for the A-subdomain that could play a role in MCM regulation; 2) interaction of a universally conserved glutamine in the N-terminal Allosteric Communication Loop with the AAA+ domain helix-2-insert (h2i); and 3) a recessed binding pocket for the MCM ssDNA-binding motif influenced by the h2i. We suggest that during helicase activation, the h2i clamps down on the leading strand to facilitate strand retention and regulate ATP hydrolysis.
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PMID:Analysis of the crystal structure of an active MCM hexamer. 2526 15


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