Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.1 (Mg2+-ATPase)
 1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transmembrane asymmetry has been extensively studied in eukaryotic cells. It is as yet only clearly demonstrated in the plasma membrane of a few cells. Subcellular organelles have evidence of lipid asymmetry, but very little consistent quantitative data exist. Proteins involved in transmembrane passage of lipids comprise enzymes of lipid metabolism and also the so-called phospholipid flippases that are either passive or active putative lipid transporters. The aminophospholipid translocase that pumps amino-phospholipids from the outer to the inner monolayer of the plasma membrane of eukaryotes is a Mg(2+)-ATP dependent protein with a high lipid selectivity. Lipid asymmetry provides an asymmetrical environment for membrane enzymes. Thus, PS (and PE) reorientation could be a way of controlling or triggering specific enzymes. Also, the asymmetrical distribution of phospholipids most likely determines the fusion-competent membranes and/or which sides of membranes should fuse. Finally, the lipid pump as well as all enzymes responsible for the net transmembrane flux of phospholipids may provide the driving force for membrane bending, notably during the formation of endocytic vesicles. Clearly, real progress in this area will be made only if the proteins of the flippase family are purified and antibodies obtained that will permit the recognition and localization of these proteins in various cells. Also, specific inhibitors as well as mutants would allow one to infer more directly what are the real functions of these proteins. At a late stage, the protein purification will eventually permit speculation on the mechanism of action of a pump that must transport simultaneously hydrophilic and hydrophobic groups through a membrane.
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PMID:Protein involvement in transmembrane lipid asymmetry. 152 72

Subsequent to myocardial infarction, cardiomyocytes within the infarcted areas and border zones expose phosphatidylserine (PS) in the outer plasma membrane leaflet (flip-flop). We showed earlier that in addition to apoptosis, this flip-flop can be reversible in cardiomyocytes. We now investigated a possible role for Rho and downstream effector Rho-associated kinase (ROCK) in the process of (reversible) PS exposure and apoptosis in cardiomyocytes. In rat cardiomyoblasts (H9c2 cells) and isolated adult ventricular rat cardiomyocytes Clostridium difficile Toxin B (TcdB), a Rho GTPase family inhibitor, C3 transferase (C3), a Rho(A,B,C) inhibitor and the ROCK inhibitors Y27632 and H1152 were used to inhibit Rho-ROCK signaling. PS exposure was assessed via flow cytometry and fluorescent digital imaging microscopy using annexin V. Akt expression and phosphorylation were analyzed via Western blot, and Akt activity was inhibited by wortmannin. The cellular concentration activated caspase 3 was determined as a measure of apoptosis, and flippase activity was assessed via flow cytometry using NBD-labeled PS. TcdB, C3, Y27632 and H1152 all significantly increased PS exposure. TcdB, Y27632 and H1152 all significantly inhibited phosphorylation of the anti-apoptotic protein Akt and Akt inhibition by wortmannin lead to increased PS exposure. However, only TcdB and C3, but not ROCK- or Akt inhibition led to caspase 3 activation and thus apoptosis. Notably, pancaspase inhibitor zVAD only partially inhibited TcdB-induced PS exposure indicating the existence of apoptotic and non-apoptotic PS exposure. The induced PS exposure coincided with decreased flippase activity as measured with NBD-labeled PS flip-flop. In this study, we show a regulatory role for a novel signaling route, Rho-ROCK-flippase signaling, in maintaining asymmetrical membrane phospholipid distribution in cardiomyocytes.
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PMID:Inhibition of Rho-ROCK signaling induces apoptotic and non-apoptotic PS exposure in cardiomyocytes via inhibition of flippase. 2069 98

Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.
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PMID:Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. 2548 57