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)

The activity of the intracellular protease, the proteasome, is modulated by a number of specific regulatory proteins. One such regulator, PA700, is a 700,000-Da multisubunit protein that activates hydrolytic activities of the proteasome via a mechanism that involves the ATP-dependent formation of a proteasome-PA700 complex. Four subunits of PA700 have been shown previously to be members of a protein family that contains a consensus sequence for ATP binding, and purified PA700 expresses ATPase activity. We report here the identification, purification, and initial characterization of a new modulator of the proteasome. The modulator has no direct effect on the activity of the proteasome, but enhances PA700 activation of the proteasome by up to 8-fold. This activation is associated with the formation of a proteasome/PA700-containing complex that is significantly larger than that formed in its absence. The modulator has a native Mr of approximately 300,000, as determined by gel filtration chromatography, and is composed of three electrophoretically distinct subunits with Mr values of 50,000, 42,000, and 27,000 (p50, p42, and p27, respectively). Amino acid sequence analysis of the subunits shows that p50 and p42 are members of the same ATP-binding protein family found in PA700. The p50 subunit is identical to TBP1, a protein previously reported to interact with human immunodeficiency virus Tat protein (Nelbock, P., Dillion, P. J., Perkins, A., and Rosen, C. A. (1990) Science 248, 1650-1653), while the p42 subunit seems to be a new member of the family. The p27 subunit has no significant sequence similarity to any previously described protein. Both p50 and p42, but not p27, were also identified as components of PA700, increasing the number of ATP-binding protein family members in this complex to six. Thus, p50 and p42 are subunits common to two protein complexes that regulate the proteasome. The PA700-dependent proteasome activator represents a new member of a growing list of proteins that regulate proteasome activity.
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PMID:Identification, purification, and characterization of a PA700-dependent activator of the proteasome. 862 9

Using a genetic strategy designed to find proteins involved in the function of the Saccharomyces cerevisiae transcriptional activator GAL4, we isolated mutants in two genes which rescue a class of gal4 activation domain mutants. One of these genes, SUG1, encodes a member of a large family of putative ATPases, the Conserved ATPase containing Domain (CAD) proteins (also known as AAA proteins) that are involved in a wide variety of cellular functions. Subsequently, SUG1 was identified as a subunit of the 26 S proteasome. We have now cloned the gene defined by the second complementation group. SUG2 encodes an essential 49-kDa protein that is also a member of the CAD family and is 43% identical to SUG1. The mutation in sug2-1, like that in sug1-1, is found in the CAD near the highly conserved ATPase motif. We present biochemical and genetic evidence that SUG2 is associated in vivo with SUG1 and is a novel CAD protein subunit of the 26 S proteasome. With its highly conserved mammalian homologs, human p42 and ground squirrel CADp44, SUG2 defines a new class of proteasomal CAD proteins.
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PMID:Isolation and characterization of SUG2. A novel ATPase family component of the yeast 26 S proteasome. 895 18

We have identified a novel protein, CADp44, based on the analysis of cDNAs derived from the brainstem of the 13-lined ground squirrel, Spermophilus tridecemlineatus. CADp44 has an unmodified molecular mass of 44,178 Da and contains multiple functional domains, including a conserved ATPase domain (CAD) and a leucine zipper motif. We show that distinct regions of the CADp44 sequence are identical to a set of peptides prepared from a recently identified bovine protein, referred to as p42, which is found in the PA700 regulatory complex of the 26S proteasome (DeMartino et al., 1996). We also show that CADp44 is the functional homolog of the newly characterized Sug2 protein from the budding yeast, Saccharomyces cerevisiae (Russell et al., 1996). Consistent with its role as a component of the 26S proteasome, CADp44 mRNA is found in all ground squirrel tissues examined. Evolutionary relationships based on sequence analysis show that both CADp44 and yeast Sug2p are distinct from the other five CAD ATPases found in the PA700, and together comprise the sixth and newest CAD subunit of the regulatory complex of the 26S proteasome.
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PMID:CADp44: a novel regulatory subunit of the 26S proteasome and the mammalian homolog of yeast Sug2p. 897 9

The 26S proteasome is a eukaryotic ATP-dependent protease functioning as a protein death machine. It is a large multisubunit complex, consisting of a catalytic 20S proteasome and two regulatory modules, named PA700. The PA700 complex is composed of multiple subunits of 25-110 kDa, which are classified into two subgroups, a subgroup of at least 6 ATPases that consitute a unique multi-gene family encoding homologous polypeptides conserved during evolution and a subgroup of approximately 15 non-ATPase subunits, most of which are structurally unrelated to each other. In the present study, we report the chromosomal localization and immunological properties of six members of the human 26S proteasomal ATPase family. By use of the fluorescence in situ hybridization method, the S4 (PSMC1), MSS1 (PSMC2), TBP1 (PSMC3), TBP7 (PSMC4), p45 (PSMC5), and p42 (PSMC6) genes were mapped to human chromosomes 19p13.3, 7q22.1-q22.3, 11p11.2, 19q13.11-q13.13, 17q23.1-q23.3, and 12q15, respectively, indicating that the genes for multiple ATPases of the 26S proteasome are located on different chromosomes. Immunoblot analysis revealed that all these ATPases were associated with the purified 26S proteasome and that some of them showed striking heterogeneity in their electrical charges.
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PMID:Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases. 947 9

We showed before that in neonatal rat cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophic growth and transcriptional regulations of genes that are markers of cardiac hypertrophy. In view of the suggested roles of Ras and p42/44 mitogen-activated protein kinases (MAPKs) as key mediators of cardiac hypertrophy, the aim of this work was to explore their roles in ouabain-initiated signal pathways regulating four growth-related genes of these myocytes, i.e. those for c-Fos, skeletal alpha-actin, atrial natriuretic factor, and the alpha3-subunit of Na+/K+-ATPase. Ouabain caused rapid activations of Ras and p42/44 MAPKs; the latter was sustained longer than 90 min. Using high efficiency adenoviral-mediated expression of a dominant-negative Ras mutant, and a specific inhibitor of MAPK kinase (MEK), activation of Ras-Raf-MEK-p42/44 MAPK cascade by ouabain was shown. The effects of the mutant Ras, an inhibitor of Ras farnesylation, and the MEK inhibitor on ouabain-induced changes in mRNAs of the four genes indicated that (a) skeletal alpha-actin induction was dependent on Ras but not on p42/44 MAPKs, (b) alpha3 repression was dependent on the Ras-p42/44 MAPK cascade, and (c) induction of c-fos or atrial natriuretic factor gene occurred partly through the Ras-p42/44 MAPK cascade, and partly through pathways independent of Ras and p42/44 MAPKs. All ouabain effects required extracellular Ca2+, and were attenuated by a Ca2+/calmodulin antagonist or a protein kinase C inhibitor. The findings show that (a) signal pathways linked to sarcolemmal Na+/K+-ATPase share early segments involving Ca2+ and protein kinase C, but diverge into multiple branches only some of which involve Ras, or p42/44 MAPKs, or both; and (b) there are significant differences between this network and the related gene regulatory pathways activated by other hypertrophic stimuli, including those whose responses involve increases in intracellular free Ca2+ through different mechanisms.
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PMID:Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. 961 40

Two activators, named PA700 and PA28, are known to bind to 20 S proteasomes, forming two different complexes. The PA700-proteasome complex, also known as the 26 S proteasome, can degrade intact proteins, whereas complexes with PA28 can degrade only peptides. Monoclonal antibodies to 20 S proteasomes or the p45 ATPase subunit (Trip1, Sug1) of PA700 precipitated the same set of proteins from HeLa extracts, including six different ATPase subunits of PA700. This shows that p45 is not present in other protein complexes and suggests that all 26 S proteasome particles contain the same set of ATPase subunits. Interferons alpha and gamma had no effect on the composition of the 26 S proteasome, except for the replacement of subunits delta, MB1 and Z with Lmp2, Lmp7 and MECL1 respectively. Surprisingly, antibodies to PA28 precipitated p42, a component of PA700. Conversely, anti-p45 antibodies precipitated not only 26 S proteasomes but also PA28 alpha, beta and gamma, indicating that 20 S proteasomes can simultaneously bind both PA700 and PA28. PA28 alpha beta is known to be involved in antigen presentation. Conceivably, intact substrate proteins are recognized by PA700 and fed into proteasomes whose cleavage specificity is optimized for antigen presentation on MHC class I by PA28 and three interferon inducible proteasome subunits.
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PMID:Simultaneous binding of PA28 and PA700 activators to 20 S proteasomes. 962 Aug 78

We have employed cDNA cloning to deduce the complete primary structure of a new subunit, designated p27, of the modulator trimer complex that stimulates the association of the PA700 regulator with the catalytic 20S proteasome to form the ATP-dependent active 26S proteasome. We found two distinct cDNAs encoding two highly homologous proteins except in the C-terminal region, which are termed tentatively p27-1 and p27-2. The short p27-2 cDNA has a deletion of 65 bp near the 3'-end region of the long p27-1 cDNA, which encodes a large protein with an extended C-terminal region, designated p27-L, whereas the long p27-1 cDNA encodes a small protein named p27-S. The polypeptides of p27-L and p27-S consist of 223 and 209 amino acid residues with calculated molecular masses of 24,852 and 22,764 and isoelectric points of 6.50 and 5.28, respectively. Immunoblot analysis with anti-p27 antibody revealed that p27, together with two other ATPase components, TBP1 and p42, was associated with not only the modulator complex but also significantly with the 26S proteasome complex, suggesting that the three are common/sharing subunits in these two complexes. By the fluorescence in situ hybridization method, the p27 (PSMD9) gene was mapped to the q24.2-q24.3 band of human chromosome 12. Computer-assisted homology analysis revealed the high sequence similarities of p27-L with a possible counterpart in Caenorhabditis elegans and Saccharomyces cerevisiae whose function is yet unknown, the yeast gene that is here termed NAS2 (non-ATPase subunit 2). Disruption of NAS2 had no effect on cell viability, indicating that the subunit is not essential for proliferation of yeast cells.
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PMID:cDNA cloning and characterization of a human proteasomal modulator subunit, p27 (PSMD9). 965 51

Each 19S regulator of the 26S proteasome contains six ATPase subunits as well as many (>14) non-ATPase protein subunits. The ATPase subunits have been detected in other complexes which may regulate transcription and possibly other cellular processes. The S10b (yeast SUG2 or human p42) and the S6' (TBP1) ATPases have been found in an activator complex (modulator) prepared from bovine red cells. We have identified and partially characterised a similar activator from different human tissues (from soluble extracts of human brain, placenta and human embryonic kidney cells) and an insect: an activator is present in soluble extracts of abdominal intersegmental muscle from Manduca sexta. Activation is ATP and concentration dependent. There is no stimulation of human red cell-derived 20S proteasome by the Manduca activator ruling out 11S regulator in the preparations. Additionally, cross-species activation occurs: the Manduca activator increases the activity of rat skeletal muscle 26S proteasomes and the human placental activator similarly increases the activity of 26S proteasomes prepared from muscles from Manduca sexta. Finally, there is no evidence for other ATPases in the activator complex.
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PMID:Activator complexes containing the proteasomal regulatory ATPases S10b (SUG2) and S6 (TBP1) in different tissues and organisms. 1036 44

We showed before that in cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca2+-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of ouabain: inductions of the genes of skeletal alpha-actin and atrial natriuretic factor, repression of the gene of the alpha3-subunit of Na+/K+-ATPase, activation of mitogen-activated protein kinases, activation of Ras-dependent protein synthesis, and activation of transcription factor NF-kappaB. Induction of c-fos and activation of AP-1 by ouabain were not sensitive to NAC. Ouabain-induced inhibition of active Rb+ uptake through Na+/K+-ATPase and the resulting rise in intracellular Ca2+ were also not prevented by NAC. A phorbol ester that also causes myocyte hypertrophy did not increase ROS generation, and its effects on marker genes and protein synthesis were not affected by NAC. We conclude the following: (a) ROS are essential second messengers within some but not all signal pathways that are activated by the effect of ouabain on Na+/K+-ATPase; (b) the ROS-dependent pathways are involved in ouabain-induced hypertrophy; (c) increased ROS generation is not a common response of the myocyte to all hypertrophic stimuli; and (d) it may be possible to dissociate the positive inotropic effect of ouabain from its growth-related effects by alteration of the redox state of the cardiac myocyte.
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PMID:Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. 1038 43

1. Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca(2+)-ATPase inhibitor, induced histamine production in a time- and concentration-dependent manner. 2. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), also enhanced histamine production. 3. alpha-Fluoromethylhistidine, a suicide substrate of L-histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production. 4. Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. 5. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6. The other MEK-1 inhibitor, U-0126, also inhibited both the thapsigargin- and TPA-induced histamine production in a concentration-dependent manner. 7. Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin- and TPA-induced increases in the HDC mRNA level. 8. These findings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin- and TPA-induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.
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PMID:Participation of mitogen-activated protein kinase in thapsigargin- and TPA-induced histamine production in murine macrophage RAW 264.7 cells. 1071 50


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