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)

Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium-ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis.
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PMID:Pathogenesis of Duchenne muscular dystrophy: the calcium hypothesis revisited. 149 54

Incubation of human red blood cell membranes (white ghosts) with N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite of acetaminophen, or with either an arylating or an oxidizing analog of NAPQI, resulted in the inhibition of membrane ion transporting systems and the modification of cytoskeletal proteins. NAPQI and 2,6-dimethyl-NAPQI, which primarily arylates protein thiols, inhibited the calmodulin-activated Ca pump ATPase activity, the basal (calmodulin-independent) Ca pump ATPase activity and the Na,K pump ATPase activity. In contrast, 3,5-dimethyl-NAPQI, which primarily oxidizes protein thiols, caused selective inhibition of the calmodulin-activated Ca pump ATPase activity. Sodium dodecyl sulfate gel electrophoresis of red blood cell (RBC) membrane proteins revealed that NAPQI and 2,6-dimethyl-NAPQI, but not 3,5-dimethyl-NAPQI, decreased the intensity of band 3 corresponding to the anion transporter, whereas NAPQI as well as 2,6-dimethyl-NAPQI, and to a lesser extent 3,5-dimethyl-NAPQI, caused a decrease of cytoskeletal protein bands, including spectrin, actin, and bands 4.1 and 4.2. These modifications were associated with increased formation of high molecular weight protein aggregates that did not enter the gel. Treatment of 3,5-dimethyl-NAPQI-exposed ghosts with the reducing agent dithiothreitol (DTT), resulted in the recovery of the affected cytoskeletal protein bands. Conversely, the modifications caused by NAPQI and 2,6-dimethyl-NAPQI were only partially reversed by DTT treatment. Taken together our results suggest that NAPQI and its two analogs modified ion transporting systems and cytoskeletal proteins by reacting with protein thiols. Both oxidation and arylation of protein thiols can alter the functional properties of important RBC membrane proteins. Of the two reactions, arylation appeared to be the less specific and more damaging event.
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PMID:Differential effects of arylating and oxidizing analogs of N-acetyl-p-benzoquinoneimine on red blood cell membrane proteins. 214 23

A study of Ca-ATPase and Ca-pump activity of the erythrocyte membrane's inverted vesicles with different cytoskeletal protein status demonstrated that Ca-pump activity remained unchanged, and Ca-ATPase activity was increased by 20-40%, as compared to erythrocytes from the normotensive controls, in hypertensive patients in the absence of exogenous calmodulin. These differences are assumed to be due to disorders of erythrocyte membrane structure in primary hypertension resulting in less efficient Ca-pump operation in the inverted vesicles. In all types of membranes obtained from hypertensive patients' erythrocytes in conditions of iso-osmotic hemolysis, calmodulin-induced increment of peak Ca-ATPase and Ca-pump activity was 2 or 3 times as low as that of normotensive controls. These differences remained in evidence after the solubilization of membrane proteins with triton X-100. No differences in calmodulin influence on Ca-ATPase affinity to Ca2+ could be found. The membranes obtained in iso-osmotic conditions demonstrated no calmodulin effect on Ca-ATPase activity which is attributed to partial proteolysis of the enzyme's molecule.
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PMID:[The Ca pump and Ca ATPase in the erythrocytes of patients with hypertension: disorders detected in cytoskeletal membranes and in solubilized Ca ATPase]. 242 39

The voltage-sensitive sodium channel is an intrinsic membrane protein that is nonrandomly distributed in neurons, suggesting a possible interaction with other cellular constituents. In this study, we have directly tested the hypothesis that components of the cytoskeleton interact with sodium channels. Utilizing the methods of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and blot overlay, we have identified a 33-kilodalton cytoskeletal protein (p33) that binds 32P-labeled sodium channel purified from rat brain. This binding is a high-affinity (KD less than 1 nM) protein-protein interaction that is blocked by low concentrations of unlabeled sodium channels but is not blocked by monosaccharides, the complex glycoprotein fetuin, the transmembrane protein Na+-K+-ATPase, or bovine serum albumin. Levels of p33 are highest in lung and spleen while lower levels are found in brain, peripheral nerve, skeletal muscle, liver, and testes. This tissue distribution implies that the sodium channel may not be the only ligand for p33.
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PMID:Identification of a 33-kilodalton cytoskeletal protein with high affinity for the sodium channel. 245 30

The intestinal absorption of calcium is certainly a complex process, dependent on several factors of which vitamin D, via 1,25(OH)2D3, is the major controlling hormone. The efficiency of calcium absorption is a function of calcium status and calcium need. As the body's demand for calcium increases, the process commonly termed, adaptation, is activated in which the synthesis of 1,25(OH)2D3 from precursor is increased, resulting in the stimulation of the rate of calcium absorption. The increased demand for calcium might result from the ingestion of a diet deficient in calcium, from growth, pregnancy, lactation and egg shell formation in the laying hen. Accomapanying the change in calcium absorptive efficiency are molecular modifications of the transporting enterocytes, some mentioned herein and elsewhere (Wasserman & Chandler, 1985; Wasserman, 1980; Wasserman et al., 1984). Highly correlated with the rate of calcium absorption under a wide variety of conditions is the concentration of the vitamin D-induced calcium-binding protein, calbindin-D28K (avian type) and calbindin-D9K (mammalian intestinal type). The role of calbindin-D in this transport process is not precisely known but is considered to act at the present time as a cytosolic facilitator of Ca2+ diffusion from the brush border membrane to the basolateral membrane. In addition to the induction of calbindin-D synthesis, 1,25(OH)2D3 exerts other effects on the intestinal epithelium that can have consequences on the calcium absorptive process. Some of these effects are summarized in Figure 14. Vitamin D-dependent reactions might be either direct effects of 1,25(OH)2D3 or indirect effects due to elevated intracellular Ca2+ concentrations. These include changes in the fluidity of the brush border membrane, an increase in microvillar alkaline phosphatase-low affinity Ca-activated ATPase activity, an association of calmodulin with the 105 kD brush border cytoskeletal protein and, following calbindin D synthesis, the binding of calbindin D to a 60 kD brush border protein and to microtubules. The latter has been suggested to be related to the proposed transfer of Ca2+ by an endocytotic-exocytotic mechanism. In addition, a vitamin D-dependent intestinal membrane calcium-binding protein has been identified (Kowarski & Schachter, 1980). Playing into this multi-component system is a stimulation of cyclic nucleotide synthesis by 1,25(OH)2D3 which, through activation of cyclic nucleotide-dependent protein kinases, might modify membrane Ca2+ "channels" by phosphorylation reactions.4+ Intracellular organelles, i.e., the endoplasmic reticulum, mitochondria, the Golgi apparatus, are potent sequesters of Ca2+ and could contribute to the protection of the cell from excessively high Ca2+ concentrations by transiently storing absorbed Ca2+.
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PMID:On the molecular mechanism of intestinal calcium transport. 254 94

Highly purified plasma membranes of calf thymocytes were fractionated by means of affinity chromatography on ouabain-Sepharose. By the method used two subfractions were obtained, one eluting freely from the affinity gel (MF1oua) and a second specifically retained by matrix-bound ouabain (MF2oua), with a total recovery of 95 per cent. Fractionation required the binding of matrix-bound ouabain to its plasma membrane receptor, i.e. (Na+ + K+)-ATPase. Increasing the temperature and binding time did not significantly alter the fractionation of plasma membranes into the two subfractions. Both plasma membrane subfractions separated by ouabain-Sepharose were of plasma membrane origin, as revealed by the identical specific activities of several membrane bound enzymes, gamma-glutamyl transpeptidase, alkaline phosphatase and Mg2+-ATPase in unseparated plasma membranes and in both subfractions, and by the identical amounts of the cytoskeletal protein actin in unseparated plasma membranes and subfractions. The plasma membrane subfractions MF1oua and MF2oua showed different structural and functional properties. In SDS-polyacrylamide gel electrophoresis polypeptides of 170, 150, 110, 94, 39, and 30 kDa were several-fold enriched in the adherent fraction, MF2oua. The phospholipid fatty acid composition of the plasma membrane subfractions proved to be different, as well. MF2oua contained significantly higher amounts of saturated fatty acids as compared to MF1oua. The specific activities of (Na+ + K+)-ATPase, Ca2+-ATPase and lysolecithin acyltransferase were highly enriched in the adherent fraction MF2oua, as compared to MF1oua. The data suggest that by the means of affinity chromatography on ouabain-Sepharose plasma membrane domains of the lymphocyte plasma membrane can be isolated, most probably implicated in the initiation of lymphocyte activation.
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PMID:Separation of plasma membrane domains of calf thymocytes by affinity chromatography on ouabain-Sepharose. 303 28

Recent work has identified a cascade of membrane bound protein kinases in Ehrlich ascites tumor cells. These enzymes, designated PKL, PKS and PKM, are present in both Ehrlich tumor and mouse brain, but the cascade is active only in the tumor tissue. We have now purified a fourth protein kinase, PKF, that is also associated with this cascade. Protein kinase F prosphorylates PKL and is phosphorylated by PKS. The position of this kinase in the cascade is as follows, where the arrows denote phosphorylation: [Formula: see text] The phosphorylation by PKF, like phosphorylation by the other kinases, is at a tyrosine residue and causes the substrate kinase (PKL) to become active. The role of the tyrosine phosphorylation in activating these kinases is described in detail elsewhere. One result of activation of the cascade is the phosphorylation of the beta subunit of the Na+K+-ATPase, which causes inefficient Na+ pumping and is at last in part responsible for the high aerobic glycolysis of Ehrlich ascites tumor cells. By several criteria protein kinase F from Ehrlich cells is homologous to the src gene product (pp60src) from avian sarcoma viruses. Antiserum raised against PKF and sera from rabbits bearing rous sarcoma virus (RSV)-induced tumors quantitatively precipitate the same 60 kd phosphoprotein from cell lysates of three different RSV-transformed cell lines. Both proteins phosphorylate PKL and a 130 kd cytoskeletal protein (vinculin). The tryptic maps of these proteins are closely similar. Both proteins bind specifically to PKL covalently coupled to Sepharose. We used this latter observation to facilitate the purification of pp60 src from RSV-transformed cells.
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PMID:A mouse homolog to the avian sarcoma virus src protein is a member of a protein kinase cascade. 616 90

In strongly-coupled models for motor enzyme function, such as the original Huxley (1957) model for muscle, ATP binding and subsequent hydrolysis are required for the detachment and reattachment of every force-producing cross-bridge. In weakly-coupled models, cross-bridges can be 'mechanically detached' without ATP binding when they have been pushed far beyond their free energy minimum and have accumulated so much strain that the attached state is less stable than the detached state. Weakly-coupled models assume that these mechanically detached cross-bridges can rejoin the pool of detached molecules that can reattach as force-producing cross-bridges, without going through an ATP hydrolysis cycle. This paper bases this assumption on a thermodynamically rigorous model for interaction between a motor enzyme molecule and binding sites on a cytoskeletal protein filament, equivalent to other examples of ligand binding interactions. It attempts to identify more clearly the features that must be added to the idea of ligand binding equilibrium to simulate a weakly-coupled motor enzyme model. Models that assume a vectorial conformational change and a longitudinal series elastic element appear to be incompatible with the assumptions of weakly-coupled cross-bridge models. A stochastic computational method has been used to examine the properties of these models. The computations have examined the behaviour of a model containing a four-state ATPase cycle, but the model is computationally a nine-state model because a force-generating attached state is allowed to equilibrate with different detached states at negative and at positive distortions, and because three adjacent sites are considered as possible attachment sites for each of the two attached states of the ATPase cycle.
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PMID:Weakly-coupled models for motor enzyme function. 755 93

Because membrane fluidity is an important determinant of membrane function, the lateral diffusion rate (DL) of the membrane protein Na,K-ATPase was determined in intact renal proximal tubule epithelial cells by the technique of fluorescence redistribution after photobleaching (FRAP). In normal cells the DL of Na,K-ATPase in the basal membrane was 3.31 x 10(-10) cm2/sec. Treatment with cytochalasin D to promote actin filament depolymerization caused a sevenfold increase in DL. Exposure of cells to a Ca(2+)-free medium or to hypoxia and reoxygenation, which have similar disruptive effects on the cytoskeleton, also caused increases in DL. Disruption of actin microfilament structure also increased the mobile fraction of Na,K-ATPase. Using a confocal laser microscopic technique only 14.9% of total Na,K-ATPase was observed to reside in the apical membrane domain of normal cells. Microfilament depolymerization caused this fraction to increase to 47.7%. Thus, the translocation of Na,K-ATPase from the basolateral to the apical domain induced by cytoskeletal protein dysfunction was enabled by an increased rate of lateral diffusion of Na,K-ATPase. The behavior of a variety of membrane lipids following actin depolymerization was more heterogeneous. Some lipids showed a similar increase in DL, whereas others showed very little dependence upon the cytoskeleton for lateral restraint.
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PMID:Lateral mobility of Na,K-ATPase and membrane lipids in renal cells. Importance of cytoskeletal integrity. 770 49

The cell division protein FtsZ, essential to initiate septum formation in Escherichia coli, is a GTPase. The thermosensitive ftsZ84 mutation, which impairs the ability of FtsZ to bind and hydrolyze GTP in vitro, maps to a short glycine-rich FtsZ segment. This region is conserved in eubacterial FtsZ homologs and is strikingly similar to the proposed GTP binding motif in the eukaryotic cytoskeletal protein tubulin. Here we show that in contrast to FtsZ, FtsZ84 protein has a Mg(2+)-dependent ATPase activity in vitro. This activity, unlike the wild-type GTPase, is specifically inhibited by sodium azide, a known antagonist of F-type ATPases and the bacterial SecA protein translocation ATPase (Oliver, D., Cabelli, R. J., Dolan, K. M., and Jarosik, G. P. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 8227-8231). Conversely, aluminum fluoride abolishes FtsZ GTPase activity but only partially affects FtsZ84 ATPase. Affinity-purified anti-FtsZ antibody blocks FtsZ84 ATPase activity, indicating that this enzymatic function is intrinsic to the mutant protein. This is, to our knowledge, the first example of a missense mutation that converts a GTPase to an ATPase.
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PMID:A point mutation converts Escherichia coli FtsZ septation GTPase to an ATPase. 808 92


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