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71.
Prasanna K. Devaraneni Gregory M. Martin Erik M. Olson Qing Zhou Show-Ling Shyng 《The Journal of biological chemistry》2015,290(12):7980-7991
Small molecules that correct protein misfolding and misprocessing defects offer a potential therapy for numerous human diseases. However, mechanisms underlying pharmacological correction of such defects, especially in heteromeric complexes with structurally diverse constituent proteins, are not well understood. Here we investigate how two chemically distinct compounds, glibenclamide and carbamazepine, correct biogenesis defects in ATP-sensitive potassium (KATP) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2. We present evidence that despite structural differences, carbamazepine and glibenclamide compete for binding to KATP channels, and both drugs share a binding pocket in SUR1 to exert their effects. Moreover, both compounds engage Kir6.2, in particular the distal N terminus of Kir6.2, which is involved in normal channel biogenesis, for their chaperoning effects on SUR1 mutants. Conversely, both drugs can correct channel biogenesis defects caused by Kir6.2 mutations in a SUR1-dependent manner. Using an unnatural, photocross-linkable amino acid, azidophenylalanine, genetically encoded in Kir6.2, we demonstrate in living cells that both drugs promote interactions between the distal N terminus of Kir6.2 and SUR1. These findings reveal a converging pharmacological chaperoning mechanism wherein glibenclamide and carbamazepine stabilize the heteromeric subunit interface critical for channel biogenesis to overcome defective biogenesis caused by mutations in individual subunits. 相似文献
72.
Ryan Roth Richard Swanson Gonzalo Izaguirre Susan C. Bock Peter G. W. Gettins Steven T. Olson 《The Journal of biological chemistry》2015,290(47):28020-28036
Past studies have suggested that a key feature of the mechanism of heparin allosteric activation of the anticoagulant serpin, antithrombin, is the release of the reactive center loop P14 residue from a native state stabilizing interaction with the hydrophobic core. However, more recent studies have indicated that this structural change plays a secondary role in the activation mechanism. To clarify this role, we expressed and characterized 15 antithrombin P14 variants. The variants exhibited basal reactivities with factors Xa and IXa, heparin affinities and thermal stabilities that were dramatically altered from wild type, consistent with the P14 mutations perturbing native state stability and shifting an allosteric equilibrium between native and activated states. Rapid kinetic studies confirmed that limiting rate constants for heparin allosteric activation of the mutants were altered in conjunction with the observed shifts of the allosteric equilibrium. However, correlations of the P14 mutations'' effects on parameters reflecting the allosteric activation state of the serpin were inconsistent with a two-state model of allosteric activation and suggested multiple activated states. Together, these findings support a minimal three-state model of allosteric activation in which the P14 mutations perturb equilibria involving distinct native, intermediate, and fully activated states wherein the P14 residue retains an interaction with the hydrophobic core in the intermediate state but is released from the core in the fully activated state, and the bulk of allosteric activation has occurred in the intermediate. 相似文献
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In spores of the Blastocladiales there is a strict temporal correlation between the breakdown of the matrix of the gamma body and the swelling of the gamma body with the duration of the spore's motility. The swelling of the gamma body upon decay is interpreted as being due to water uptake. The swollen gamma bodies fuse with the plasmalemma and expel their content. We suggest that the swelling of the gamma body and its subsequent fusion with the plasmalemma of the spore are the means by which the spores of the Blastocladiales maintain osmotic balance with the medium in which they swim. The decay of the gamma body during the motile period of the spore is a separate and distinct process, not related to the mobilization of the remaining gamma bodies during encystment and cell wall formation. 相似文献
77.
M Nechad L Olson 《Biology of the cell / under the auspices of the European Cell Biology Organization》1983,48(2-3):167-174
The relationship between brown adipose tissue (BAT) and its sympathetic innervation during development was investigated by transplantation of undifferentiated (white fat-like) hamster BAT into the anterior eye chamber of adult hamsters. Such transplants are known to be revascularized and reinnervated by the vessels and the nerves of the host iris. The morphology of the BAT transplants was analysed during the post-operative weeks by light and electron microscopy, and the ingrowth of sympathetic nerve fibres from the iris was followed by radioautography. BAT appeared to differentiate in oculo, i.e. presented increasing amounts of adipocytes with multilocular fat deposits and abundant, well-developed mitochondria, but only after a delay of approx. 10 days, and remained much fatter than in situ. The establishment of the sympathetic innervation was not synchronous with the revascularization process. It occurred simultaneously with the morphological differentiation of the BAT transplants, and the nerve fibre density remained low. In the absence of sympathetic innervation, i.e. when the host irides were sympathectomized prior to transplantation, BAT still differentiated, but the process was further delayed and the proportion of differentiated brown adipocytes after 20 days in oculo was clearly lower than in control transplants. It is concluded that the sympathetic innervation in BAT is involved in the regulation of differentiating activity in the tissue, but is not obligatory for differentiation to occur. 相似文献
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This article is the fifth installment in an annual series of reviews of successive year's research dealing with the endogenous opiate peptides. Due to the continuing massive increase in the number of studies in this field, it has become impossible to continue comprehensive reviews of all aspects of this work. As a result we have decided that beginning this year the coverage will be abbreviated to emphasize non-analgesic and behavioral work. The specific areas discussed include stress, tolerance and dependence, consummatory responses, alcohol consumption, schizophrenia and emotional disorders, learning and memory, cardiovascular responses, respiratory effects, thermoregulatory effects, neurological deficits and other disorders, activity, and other, miscellaneous behaviors. As in previous years, we have attempted a relatively comprehensive review of the subjects covered only for the previous year and have not made an attempt to evaluate their contributions relative to those of past years. 相似文献
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