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131.
T J Andreasen  M G McNamee 《Biochemistry》1980,19(20):4719-4726
The characteristics of fatty acid inhibition of acetylcholine receptor function were examined in membrane vesicles prepared from Torpedo californica electroplax. Inhibition of the carbamylcholine-induced increase in sodium ion permeability was correlated with the bulk melting point of exogenously incorporated fatty acids. Above its melting temperature, a fatty acid could inhibit the large increase in cation permeability normally elicited by agonist binding to receptor. Below its melting temperature, a fatty acid was ineffective. None of the fatty acids altered any of the ligand binding properties of the receptor. Inhibitory fatty acids did not induce changes in membrane fluidity, as determined by electron paramagnetic resonance using spin-labeled fatty acids. The spin-labeled fatty acids also acted as inhibitors, and the extent of inhibition depended largely on the position of the nitroxide group along the fatty acid chain. Addition of noninhibitory fatty acid to the vesicle membranes did not protect the receptor from inhibition by spin-labeled fatty acids. The effects of free fatty acids on acetylcholine receptor function are attributed to the disruptions of protein-lipid interactions.  相似文献   
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Summary cAMP dependent protein kinase and cAMP independent synthase kinase incorporated up to two Pi/subunit in rabbit skeletal muscle glycogen synthase I. The first Pi/subunit was incorporated much faster than the second. After incorporation of one Pi/subunit by the CAMP dependent protein kinase, the ratio of independence (RI) was 0.20 and the dissociation constant Kc for Glc-6-P was 0.3 mm, and quite different from the RI of 0.02 and Kc (Glc-6-P) of 1 mM, obtained when one Pi/subunit was incorporated by the cAMP independent synthase kinase. Within the first Pi/subunit, the cAMP dependent protein kinase predominantly phosphorylated in the trypsin sensitive region (60–70%), corresponding to two trichloro-acetic acid soluble tryptic phosphopeptides, termed site-1 and site-2. Site-2 was found to be phosphorylated prior to site-1. CNBr degradation resolved the phosphorylated regions in two phosphopeptides with Mr 28,000 and 10,000.The larger CNBr phosphopeptides were derived from the trypsin sensitive region. Within the first Pi/subunit, synthase kinase almost exclusively phosphorylated in the trypsin insensitive region (80%) corresponding to the smaller CNBr phosphopeptide. However, when two Pi/subunit were incorporated by either the cAMP dependent protein kinase or the synthase kinase the phosphates were almost equally distributed between the trypsin sensitive and insensitive regions and Kc (Glc-6-P) increased to 2 mm, Maximum phosphorylation (2.8–3.3 Pi/subunit and Kc (Glc-6-P) 9–11 mm) was only obtainable when both the cAMP dependent protein kinase and the synthase kinase were present.The phosvitin kinase very slowly incorporated one Pi/subunit.We suggest that within the first P1subunit phosphorylation in the trypsin insensitive region determine the affinity for the allosteric activator, glucose-6-phosphate. Thereafter phosphorylation in the trypsin sensitive region is the major determinant. Purified glycogen-free rabbit skeletal muscle glycogen synthase binds glycogen with lower affinity than polymorphonuclear leukocyte glycogen synthase. Glycogen was found to increase the initial rate of phosphorylation and facilitate the phosphorylation of site-1.Abbreviations cAMP adenosine cyclic 3:5-monophosphate - Glc-6-P glucose-6-phosphate - UDP-Glc uridine 5-diphosphoglucose - EGTA ethylene glycol-bis(-aminoethylether)-N,N-tetraacetic acid - EDTA ethylenediamine tetraacetic acid - CNBr cyanogen bromide - DTT dithiothreitol - SDS sodium dodecyl sulphate - RI ratio of independence  相似文献   
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The PI3-kinase/Akt pathway is an important cell survival pathway that is deregulated in the majority of human cancers. Despite the apparent druggability of several kinases in the pathway, no specific catalytic inhibitors have been reported in the literature. The authors describe the development of a fluorometric imaging plate reader (FLIPR)-based Akt1 translocation assay to discover inhibitors of Akt1 activation. Screening of a diverse chemical library of 45,000 compounds resulted in identification of several classes of Akt1 translocation inhibitors. Using a combination of classical in vitro assays and translocation assays directed at different steps of the Akt pathway, the mechanisms of action of 2 selected chemical classes were further defined. Protein translocation assays emerge as powerful tools for hit identification and characterization.  相似文献   
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Vitronectin (VN) and plasminogen activator inhibitor-1 (PAI-1) have important functional interactions: VN stabilises the protease inhibitory activity of PAI-1 and PAI-1 inhibits binding of adhesion receptors to VN. Having previously mapped the PAI-1 binding area for VN, we have now constructed a PAI-1 variant, R103A-M112A-Q125A, without measurable affinity to VN, but with full protease inhibitory activity and endocytosis receptor binding. As a tool for evaluating the physiological and pathophysiological functions of the PAI-1-VN interaction, our new variant is far superior to the previously widely used PAI-1 variant Q125K, which we have found possesses an only about 10-fold reduced affinity to VN.  相似文献   
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Influenza in humans is characterised by strongly annual dynamics and antigenic evolution leading to partial escape from prior host immunity. The variability of new epidemic strains depends on the amount of virus currently circulating. In this paper, the amount of antigenic variation produced each year is dependent on the epidemic size. Our model reduces to a one-dimensional map and a full mathematical analysis is presented. This simple system suggests some basic principles which may be more generally applicable. In particular, for diseases with antigenic drift, vaccination may be doubly beneficial. Not only does it protect the population through classical herd immunity, but the overall case reduction reduces the chance of new variants being produced; hence, subsequent epidemics may be milder as a result of this positive feedback. Also, a disease with a high innate rate of antigenic variation will always be able to invade a susceptible population, whereas a disease with less potential for variation may require several introduction events to become endemic.  相似文献   
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