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)

Yeast protein insertion orientation (PIO) mutants were isolated by selecting for growth on sucrose in cells in which the only source of invertase is a C-terminal fusion to a transmembrane protein. Only the fraction with an exocellular C terminus can be processed to secreted invertase and this fraction is constrained to 2-3% by a strong charge difference signal. Identified pio mutants increased this to 9-12%. PIO1 is SPF1, encoding a P-type ATPase located in the endoplasmic reticulum (ER) or Golgi. spf1-null mutants are modestly sensitive to EGTA. Sensitivity is considerably greater in an spf1 pmr1 double mutant, although PIO is not further disturbed. Pmr1p is the Golgi Ca(2+) ATPase and Spf1p may be the equivalent ER pump. PIO2 is STE24, a metalloprotease anchored in the ER membrane. Like Spf1p, Ste24p is expressed in all yeast cell types and belongs to a highly conserved protein family. The effects of ste24- and spf1-null mutations on invertase secretion are additive, cell generation time is increased 60%, and cells become sensitive to cold and to heat shock. Ste24p and Rce1p cleave the C-AAX bond of farnesylated CAAX box proteins. The closest paralog of SPF1 is YOR291w. Neither rce1-null nor yor291w-null mutations affected PIO or the phenotype of spf1- or ste24-null mutants. Mutations in PIO3 (unidentified) cause a weaker Pio phenotype, enhanced by a null mutation in BMH1, one of two yeast 14-3-3 proteins.
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PMID:Yeast genes controlling responses to topogenic signals in a model transmembrane protein. 1195 Sep 29

We have determined effect of the oxidant peroxynitrite (ONOO-) on Ca2+-dependent matrix metalloprotease-2 (MMP-2) activity and the role of the protease on Ca2+ ATPase activity in bovine pulmonary vascular smooth muscle plasma membrane under ONOO- -triggered conditions. The smooth muscle plasma membrane possesses a 72-kDa protease activity in a gelatin-containing zymogram. The 72-kDa protease activity has been found to be inhibited by tissue inhibitor of metalloprotease-2 (TIMP-2), indicating that the protease is the matrix metalloprotease-2 (MMP-2). Treatment of the membrane suspension with ONOO- caused stimulation of the MMP-2 activity (as evidenced by 14C-gelatin degradation) and also increased Ca2+ ATPase activity. The ONOO- -triggered protease activity and the Ca2+ ATPase activity were found to be inhibited by the antioxidants: vitamin E, thiourea, and mannitol. Pretreatment with catalase and superoxide dismutase did not significantly alter ONOO- -stimulated MMP-2 activity and Ca2+ATPase activity, indicating that peroxide and superoxide are not present in appreciable amount in ONOO-. Under both basal and ONOO- triggered conditions, the MMP-2 activity and the Ca2+ ATPase activity were also inhibited by EGTA, 1:10-phenanthroline, and TIMP-2. However, the ONOO- -stimulated MMP-2 activity and the Ca2+ ATPase activity were found to be insensitive to phenylmethylsulfonylfluoride, Bowman-Birk inhibitor, chymostatin, leupeptin, antipain, N-ethylmaleimide, and pepstatin. These results suggest that ONOO- caused stimulation of MMP-2 activity and that the increased MMP-2 activity subsequently played a pivotal role in stimulating Ca2+ ATPase activity in bovine pulmonary vascular smooth muscle plasma membrane.
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PMID:Role of Ca2+-dependent metalloprotease-2 in stimulating Ca2+ ATPase activity under peroxynitrite treatment in bovine pulmonary artery smooth muscle membrane. 1210 73

FtsH, a membrane-bound metalloprotease, with cytoplasmic metalloprotease and AAA ATPase domains, degrades both soluble and integral membrane proteins in Escherichia coli. In this paper we investigated how membrane-embedded substrates are recognized by this enzyme. We showed previously that FtsH can initiate processive proteolysis at an N-terminal cytosolic tail of a membrane protein, by recognizing its length (more than 20 amino acid residues) but not exact sequence. Subsequent proteolysis should involve dislocation of the substrates into the cytosol. We now show that this enzyme can also initiate proteolysis at a C-terminal cytosolic tail and that the initiation efficiency depends on the length of the tail. This mode of degradation also appeared to be processive, which can be aborted by a tightly folded periplasmic domain. These results indicate that FtsH can exhibit processivity against membrane-embedded substrates in either the N-to-C or C-to-N direction. Our results also suggest that some membrane proteins receive bidirectional degradation simultaneously. These results raise intriguing questions about the molecular directionality of the dislocation and proteolysis catalyzed by FtsH.
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PMID:Membrane protein degradation by FtsH can be initiated from either end. 1216 2

FtsH is a cytoplasmic membrane-integrated, ATP-dependent metalloprotease, which processively degrades both cytoplasmic and membrane proteins in concert with unfolding. The FtsH protein is divided into the N-terminal transmembrane region and the larger C-terminal cytoplasmic region, which consists of an ATPase domain and a protease domain. We have determined the crystal structures of the Thermus thermophilus FtsH ATPase domain in the nucleotide-free and AMP-PNP- and ADP-bound states, in addition to the domain with the extra preceding segment. Combined with the mapping of the putative substrate binding region, these structures suggest that FtsH internally forms a hexameric ring structure, in which ATP binding could cause a conformational change to facilitate transport of substrates into the protease domain through the central pore.
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PMID:Hexameric ring structure of the ATPase domain of the membrane-integrated metalloprotease FtsH from Thermus thermophilus HB8. 1237 27

The ftsH gene, present in all eubacterial species, is anchored in the cytoplasmic membrane and contains an ATP- and a Zn-binding domain that are both part of a metalloprotease activity. The Bacillus subtilis ftsH is not essential, but null mutants exhibit a pleiotropic phenotype including filamentous growth; hypersensitivity towards heat and salt stress and a failure to sporulate. To find out whether one or the other functional domain is involved in these different phenotypes, point mutations were introduced into the coding region for both domains leading to a replacement of conserved amino acid residues. The mutant alleles were fused to a xylose-inducible promoter and integrated ectopically into two different strains, one expressing the wild-type ftsH allele and the other carrying a ftsH knockout. While none of the strains exhibited a growth defect in rich medium at 37 degrees C, those strains expressing only the mutant alleles did not resume growth after heat or salt stress challenge. Furthermore, none of the mutant alleles promoted sporulation. While only those purified mutant FtsH proteins with an intact Walker A box exhibited ATPase activity, all of them failed to degrade beta-casein.
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PMID:Construction and analyses of mutant ftsH alleles of Bacillus subtilis involving the ATPase- and Zn-binding domains. 1538 1

FtsH is a cytoplasmic membrane protein that has N-terminally located transmembrane segments and a main cytosolic region consisting of AAA-ATPase and Zn2+-metalloprotease domains. It forms a homo-hexamer, which is further complexed with an oligomer of the membrane-bound modulating factor HflKC. FtsH degrades a set of short-lived proteins, enabling cellular regulation at the level of protein stability. FtsH also degrades some misassembled membrane proteins, contributing to their quality maintenance. It is an energy-utilizing and processive endopeptidase with a special ability to dislocate membrane protein substrates out of the membrane, for which its own membrane-embedded nature is essential. We discuss structure-function relationships of this intriguing enzyme, including the way it recognizes the soluble and membrane-integrated substrates differentially, on the basis of the solved structure of the ATPase domain as well as extensive biochemical and genetic information accumulated in the past decade on this enzyme.
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PMID:Cellular functions, mechanism of action, and regulation of FtsH protease. 1591 Feb 74

We have previously reported a new group of AAA proteins, which is only found in Archaeoglobus and methanogenic archaea (AMA). The proteins are phylogenetically basal to the metalloprotease clade and their N-terminal domain is homologous to the beta-clam part of the N-domain of CDC48-like proteins. Here we report the biochemical and biophysical characterization of Archaeoglobus fulgidus AMA, and of its isolated N-terminal (AMA-N) and ATPase (AMA-DeltaN) domains. AfAMA forms hexameric complexes, as does AMA-N, while AMA-DeltaN only forms dimers. The ability to hexamerize is dependent on the integrity of a GYPL motif in AMA-N, which resembles the pore motif of FtsH and HslU. While the physiological function of AMA is unknown, we show that it has ATP-dependent chaperone activity and can prevent the thermal aggregation of proteins in vitro. The ability to interact with non-native proteins resides in the N-domain and is energy-independent.
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PMID:Characterization of AMA, a new AAA protein from Archaeoglobus and methanogenic archaea. 1673 Apr 57

In the present study we have identified a new metalloprotease encoded by the nuclear ATP23 gene of Saccharomyces cerevisiae that is essential for expression of mitochondrial ATPase (F(1)-F(O) complex). Mutations in ATP23 cause the accumulation of the precursor form of subunit 6 and prevent assembly of F(O). Atp23p is associated with the mitochondrial inner membrane and is conserved from yeast to humans. A mutant harboring proteolytically inactive Atp23p accumulates the subunit 6 precursor but is nonetheless able to assemble a functional ATPase complex. These results indicate that removal of the subunit 6 presequence is not an essential event for ATPase biogenesis and that Atp23p, in addition to its processing activity, must provide another important function in F(O) assembly. The product of the yeast ATP10 gene was previously shown to interact with subunit 6 and to be required for its association with the subunit 9 ring. In this study one extra copy of ATP23 was found to be an effective suppressor of an atp10 null mutant, suggesting an overlap in the functions of Atp23p and Atp10p. Atp23p may, therefore, also be a chaperone, which in conjunction with Atp10p mediates the association of subunit 6 with the subunit 9 ring.
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PMID:The metalloprotease encoded by ATP23 has a dual function in processing and assembly of subunit 6 of mitochondrial ATPase. 1713 90

Trichophyton rubrum is a cosmopolitan and anthropophilic fungus able to invade keratinized tissue, causing infection in human skin and nails. This work evaluated the changes in the extracellular pH during its growth in keratin (after 6, 12, 24, 48, 72h and 7 days) at initial pH 5.0. We observed a gradual increase of basal pH under keratin exposure when compared to glucose condition. Also, we identified 576T. rubrum transcripts differentially expressed by subtractive suppression hybridization (SSH) using conidia cultivated for 72h in keratin as tester, and cultivated in glucose as driver. The over-expression of 238 transcripts obtained under keratin condition was confirmed by macro-array dot-blot, revealing 28 unigenes. Putative proteins encoded by these genes showed similarity to fungi proteins involved in basic metabolism, growth and virulence, i.e., transporters ABC-MDR, MFS and ATPase of copper, NIMA interactive protein, Gag-Pol polyprotein, virulence factors serine-protease subtilisin and metalloprotease, cytochrome P450, GlcN-6-phosphate deaminase and Hsp30. The upregulation of T. rubrum genes encoding subtilisin, metalloprotease and Gag-Pol polyprotein was also validated by northern blot. The results of this study provide the first insight into genes differentially expressed during T. rubrum grown in keratin that may be involved in fungal pathogenesis.
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PMID:Isolation of transcripts over-expressed in human pathogen Trichophyton rubrum during growth in keratin. 1759 Mar 7

Cancer immunotherapy relies on the identification and characterization of tumour antigens that can be recognized by effector T cells. Here, we used a proteomics-based approach to identify tumour antigens recognized by serum antibodies from patients with breast cancer. Specific reactivity against a set of spots was identified and their identity was revealed by MALDI-TOF peptide mass fingerprinting. They include disintegrin and metalloprotease 10, aldolase A, beta-ATPase F1, heat shock protein 27, deaminase, pyruvate dehydrogenase protein X component, and Vimentin. Western blot analysis using recombinant proteins expressed in E. coli confirmed the specific reactivity with patient sera. Several tumour antigens were expressed on the surface of the T7 phage and shown to trigger specific immune responses in BALB/c mice following oral immunisation. Furthermore, these immune responses inhibited tumour growth and metastasis of the 4T1 mammary adenocarcinoma cell line. Collectively, the present data indicate that proteomics-based strategy can identify tumour antigens whose surface display on phages or bacteria can provide an effective strategy for mucosal cancer vaccines. In addition, arrayed phage-displayed tumour antigens could be useful as a serum-based screening test for the detection of several tumour antigens.
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PMID:Mucosal vaccination with phage-displayed tumour antigens identified through proteomics-based strategy inhibits the growth and metastasis of 4T1 breast adenocarcinoma. 1809 64


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