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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, the role of YidC in the membrane protein biogenesis of the F(0) sector of the Escherichia coli F(1)F(0) ATP synthase was investigated. Whereas subunits a and c of the F(1)F(0) ATP synthase were strictly dependent on YidC for membrane insertion, subunit b required YidC for efficient insertion (Yi, L., Jiang, F., Chen, M., Cain, B., Bolhuis, A., and Dalbey, R. E. (2003) Biochemistry 42, 10537-10544). In this paper, we investigated other protein components and energetics that are required in the membrane protein assembly of the F(0) sector subunits. We show here that the Sec translocase and the signal recognition particle (SRP) pathway are required for membrane insertion of subunits a and b. In contrast, subunit c required neither the Sec machinery nor the SRP pathway for insertion. While the proton motive force was not required for insertion of subunits b and c, it was required for translocation of the negatively charged periplasmic NH(2)-terminal tail of subunit a, whereas periplasmic loop 2 of subunit a could insert in a proton motive force-independent manner. Taken together, the in vivo data suggest that subunits a and b are inserted by the Sec/SRP pathway with the help of YidC, and subunit c is integrated into the membrane by the novel YidC pathway.
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PMID:Sec/SRP requirements and energetics of membrane insertion of subunits a, b, and c of the Escherichia coli F1F0 ATP synthase. 1526 11

The mitochondrial ATP synthase is a membrane protein complex which couples the proton gradient across the mitochondrial inner membrane to the synthesis of ATP from ADP+Pi. The complex is composed of essential subunits for its motor functions and supernumerary subunits, the roles of which remain to be elucidated. Subunits g and A6L are supernumerary subunits, and the specific roles of these subunits are still matters of debate. To gain insight into the functions of these two subunits, we carried out the alignment and the homolog search of the protein sequences of the subunits and found the following features: Subunit g appears to have isoforms in animals, and the transmembrane domain of the animal subunit g contains a completely conserved acidic residue in the middle of a helix on the conserved side of the transmembrane helix. This finding implicates the conserved acidic residue as important for the function of subunit g. The alignment of A6L protein sequences shows a conserved aromatic residue at the N-terminal domain with which the N-terminal MPQL sequence comprises a unique MPQLX4Ar motif that can signify the protein A6L. The conserved aromatic residue may also be important for the function of A6L.
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PMID:Mitochondrial ATP synthase: a bioinformatic approach reveals new insights about the roles of supernumerary subunits g and A6L. 1569 30

Clear-native PAGE (CN-PAGE) separates acidic water-soluble and membrane proteins (pI < 7) in an acrylamide gradient gel, and usually has lower resolution than blue-native PAGE (BN-PAGE). The migration distance depends on the protein intrinsic charge, and on the pore size of the gradient gel. This complicates estimation of native masses and oligomerization states when compared to BN-PAGE, which uses negatively charged protein-bound Coomassie-dye to impose a charge shift on the proteins. Therefore, BN-PAGE rather than CN-PAGE is commonly used for standard analyses. However, CN-PAGE offers advantages whenever Coomassie-dye interferes with techniques required to further analyze the native complexes, e.g., determination of catalytic activities, as shown here for mitochondrial ATP synthase, or efficient microscale separation of membrane protein complexes for fluorescence resonance energy transfer (FRET) analyses. CN-PAGE is milder than BN-PAGE. Especially the combination of digitonin and CN-PAGE can retain labile supramolecular assemblies of membrane protein complexes that are dissociated under the conditions of BN-PAGE. Enzymatically active oligomeric states of mitochondrial ATP synthase previously not detected using BN-PAGE were identified by CN-PAGE.
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PMID:Advantages and limitations of clear-native PAGE. 1622 May 35

The salt-mediated-stress response in Rhodobacter sphaeroides f. sp. denitrificans IL 106 was investigated by culturing cells in the presence and in the absence of NaCl in growth media. Fractionation of cells followed by SDS-PAGE and 2D-PAGE revealed an increase in the levels of membrane proteins of 39 and 50 kDa and a decrease in the level of a membrane protein of 52 kDa with increasing levels of external NaCl. The proteins were isolated and sequenced. The polypeptide of 50 kDa in the inner membrane was assigned to an ATP synthase beta chain and that of 52 kDa in the outer membrane to a flagellar filament protein. As the N terminal of the 39 kDa protein in the outer membrane was blocked, partial proteolysis was carried out and four peptides were sequenced. Each sequence exhibited no significant homology with those available in databases, suggesting that the polypeptide of 39 kDa (named SspA) is a novel salt-stress-induced protein.
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PMID:Salt-stress-responsive membrane proteins in Rhodobacter sphaeroides f. sp. denitrificans IL 106. 1623 81

V-ATPases are multisubunit membrane protein complexes that use the energy provided by ATP hydrolysis to generate a proton gradient across various intracellular and plasma membranes. In doing so, they maintain an acidic pH in the lumen of intracellular organelles and acidify extracellular milieu to support specific cellular functions. V-ATPases are structurally similar to the F1F0-ATP synthase, with an intrinsic membrane domain (V0) and an extrinsic peripheral domain (V1) joined by several connecting elements. To gain a clear functional understanding of the catalytic mechanism, and of the stability requirements for regulatory processes in the enzyme, a clear topology of the enzyme has to be established. In particular, the composition and arrangement of the peripheral stator subunits must be firmly settled, as these play specific roles in catalysis and regulation. We have designed a strategy allowing us to coexpress different combinations of these subunits to delineate specific interactions. In this study, we report the interaction between the peripheral stator EG complex and subunits C and H of the V-ATPase from the yeast Saccharomyces cerevisae. A combination of analytical gel filtration, native gel electrophoresis, and ultracentrifugation analysis allowed us to ascertain the homogeneity and molar mass of the purified EGC complex as well as of the EG complex, supporting the formation of 1:1(:1) stoichiometric complexes. The EGC complex can be formed in vitro by combining equimolar amounts of subunit C and the EG subcomplex and results most likely from the initial interaction between subunits E and C.
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PMID:Peripheral stator of the yeast V-ATPase: stoichiometry and specificity of interaction between the EG complex and subunits C and H. 1631 93

The transformation of the electrochemical membrane proton gradient into the energy of chemical bond in adenosinetriphosphate is one of the most important biological processes occurring in the living cell. The main enzyme that directly catalyzes the synthesis of ATP from ADP and Pi in aerobic conditions is F0F1-ATP synthase. In the present study, conformational changes in membrane protein part of ATP synthase during its catalytic cycle were described in terms of dynamic equations of solid state rotation. It was shown that this process should be considered in the framework of classical mechanics. The time dependences of the angle rotation for the protein complex rotates around its central axis were oobtained. Possible types of rotation were analyzed. It was proved that, considering the modern level of knowledge and understanding of ATP synthase structure and function are taken into account, the minimal period of rotor turnover cannot be less than 10(-9) s. With regard for viscous friction and elastic tension in the central axis, the calculated time of whole turnover varies from 10(-6) to 10(-3) and depends on the set of parameters used. These results indicate the essential contribution of friction and elastic tension to the rotation dynamics of the rotor. It is suggested that the proposed model can be used as a part of the entire algorithm for computer simulation of ATP synthase.
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PMID:[A mathematical model of conformational changes in membrane protein part of F0F1-ATP synthase]. 1635 84

Syringomycin, a peptide toxin produced by the phytopathogen Pseudomonas syringae pv syringae preferentially stimulated (2-fold) the vanadate-sensitive ATPase activity associated with the plasma membrane of red beet storage tissue. The toxin had a very slight effect on the tonoplast ATPase and had no detectable effect on the mitochondrial ATPase. Optimal stimulation was achieved with 10 to 50 micrograms of syringomycin per 25 micrograms of membrane protein. Treatment of membranes with 0.1% (weight/volume) deoxycholate eliminated the activation effect, and enzyme solubilized with Zwittergent 3-14 was not affected by syringomycin. ATPase activity was activated to the same extent at KCl concentrations ranging from 0 to 50 millimolar. Valinomycin, nigericin, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and gramicidin did not increase the plasma membrane ATPase activity. However, these ionophores did not hinder the ability of syringomycin to stimulate the activity. We suggest that syringomycin does not increase ATPase activity by altering membrane ion gradients nor directly interacting with the enzyme, but possibly through regulatory effectors or covalent modification of the enzyme.
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PMID:Mechanism of Action of Pseudomonas syringae Phytotoxin, Syringomycin : Stimulation of Red Beet Plasma Membrane ATPase Activity. 1666 11

Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3(Deltaex7/8) knock-in mice and CbCln3(Deltaex7/8) cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wildtype cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.
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PMID:Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. 1671 84

YidC is a member of the OxaI family of membrane proteins that has been implicated in the membrane insertion of inner membrane proteins in Escherichia coli. We have recently demonstrated that proteoliposomes containing only YidC support both the stable membrane insertion and the oligomerization of the c subunit of the F(1)F(0) ATP synthase (F(0)c). Here we have shown that two mutants of F(0)c unable to form a functional F(1)F(0) ATPase interact with YidC, require YidC for membrane insertion, but fail to oligomerize. These data show that oligomerization is not essential for the stable YidC-dependent membrane insertion of F(0)c consistent with a function of YidC as a membrane protein insertase.
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PMID:YidC-mediated membrane insertion of assembly mutants of subunit c of the F1F0 ATPase. 1688 Feb 4

We recently identified polynucleotide phosphorylase (PNPase) as a potential binding partner for the TCL1 oncoprotein. Mammalian PNPase exhibits exoribonuclease and poly(A) polymerase activities, and PNPase overexpression inhibits cell growth, induces apoptosis, and stimulates proinflammatory cytokine production. A physiologic connection for these anticancer effects and overexpression is difficult to reconcile with the presumed mitochondrial matrix localization for endogenous PNPase, prompting this study. Here we show that basal and interferon-beta-induced PNPase was efficiently imported into energized mitochondria with coupled processing of the N-terminal targeting sequence. Once imported, PNPase localized to the intermembrane space (IMS) as a peripheral membrane protein in a multimeric complex. Apoptotic stimuli caused PNPase mobilization following cytochrome c release, which supported an IMS localization and provided a potential route for interactions with cytosolic TCL1. Consistent with its IMS localization, PNPase knockdown with RNA interference did not affect mitochondrial RNA levels. However, PNPase reduction impaired mitochondrial electrochemical membrane potential, decreased respiratory chain activity, and was correlated with altered mitochondrial morphology. This resulted in FoF1-ATP synthase instability, impaired ATP generation, lactate accumulation, and AMP kinase phosphorylation with reduced cell proliferation. Combined, the data demonstrate an unexpected IMS localization and a key role for PNPase in maintaining mitochondrial homeostasis.
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PMID:Mammalian polynucleotide phosphorylase is an intermembrane space RNase that maintains mitochondrial homeostasis. 1696 81


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