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排序方式: 共有446条查询结果,搜索用时 15 毫秒
91.
Rudenko IN Kaganovich A Hauser DN Beylina A Chia R Ding J Maric D Jaffe H Cookson MR 《The Biochemical journal》2012,446(1):99-111
Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2-3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD. 相似文献
92.
Faour WH He Q Mancini A Jovanovic D Antoniou J Di Battista JA 《The Journal of biological chemistry》2006,281(29):19849-19860
Cyclooxygenase-2 (COX-2) overexpression has been linked to cell survival, transformation, and hyperproliferation. We examined the regulation of the tumor suppressor gene p53 and p53 target genes by prostaglandin E(2) (PGE(2)) in human synovial fibroblasts (HSF). PGE(2) induced a time-dependent increase in p53 Ser(15) phosphorylation, with no discernible change in overall p53 levels. PGE(2)-dependent Ser(15) phosphorylation was apparently mediated by activated p38 MAP kinase as SB202190, a p38 kinase inhibitor, blocked the response. Overexpression of a MKK3 construct, but not MKK1, stimulated SB202190-sensitive p53 Ser(15) phosphorylation. PGE(2)-stimulated [phospho-Ser(15)]p53 transactivated a p53 response element (GADD45)-luciferase reporter in transiently transfected HSF (SN7); the effect was compromised by overexpression of a dominant-negative mutant (dnm) of p53 or excess p53S15A expression plasmid but mimicked by a constitutively active p53S15E expression construct. PGE(2), wtp53 expression in the presence of PGE(2), and p53S15E suppressed steady-state levels of MEKK1-induced MMP-1 mRNA, effects nullified with co-transfection of p53 dnm or p53S15A. MEKK1-induced MMP-1 promoter-driven luciferase activity was largely dependent on a c/EBPbeta-NF-kappaB-like enhancer site at -2008 to -1972 bp, as judged by deletion and point mutation analyses. PGE(2), overexpression of p53wt with PGE(2), or p53S15E abolished the MEKK1-induced MMP-1 promoter luciferase activity. Gel-shift/super gel-shift analyses identified c/EBPbeta dimers and c/EBPbeta/NF-kappaB p65 heterodimers as binding species at the apparent site of MEKK1-dependent transactivation. PGE(2)-stimulated [phospho-Ser(15)]p53 abrogated the DNA binding of c/EBPbeta dimers and c/EBPbeta/NF-kappaB p65 heterodimers. Our data suggest that COX-2 prostaglandins may be implicated in p53 function and p53 target gene expression. 相似文献
93.
Cytochrome c oxidase is a redox-driven proton pump which converts atmospheric oxygen to water and couples the oxygen reduction reaction to the creation of a membrane proton gradient. The structure of the enzyme has been solved; however, the mechanism of proton pumping is still poorly understood. Recent calculations from this group indicate that one of the histidine ligands of enzyme's CuB center, His291, may play the role of the pumping element. In this paper, we report on the results of calculations that combined first principles DFT and continuum electrostatics to evaluate the energetics of the key energy generating step of the model-the transfer of the chemical proton to the binuclear center of the enzyme, where the hydroxyl group is converted to water, and the concerted expulsion of the proton from delta-nitrogen of His291 ligand of CuB center. We show that the energy generated in this step is sufficient to push a proton against an electrochemical membrane gradient of about 200 mV. We have also re-calculated the pKa of His291 for an extended model in which the whole Fe(a3)-CuB center with their ligands is treated by DFT. Two different DFT functionals (B3LYP and PBE0), and various dielectric models of the protein have been used in an attempt to estimate potential errors of the calculations. Although current methods of calculations do not allow unambiguous predictions of energetics in proteins within few pKa units, as required in this case, the present calculation provides further support for the proposed His291 model of CcO pump and makes a specific prediction that could be targeted in the experimental test. 相似文献
94.
Tran JA Pontillo J Fleck BA Marinkovic D Arellano M Tucci FC Lanier M Saunders J Jiang W Chen CW Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2006,16(14):3693-3696
A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency. 相似文献
95.
Thomas Wicker Simon G. Krattinger Evans S. Lagudah Takao Komatsuda Mohammad Pourkheirandish Takashi Matsumoto Sylvie Cloutier Laurenz Reiser Hiroyuki Kanamori Kazuhiro Sato Dragan Perovic Nils Stein Beat Keller 《Plant physiology》2009,149(1):258-270
A large number of wheat (Triticum aestivum) and barley (Hordeum vulgare) varieties have evolved in agricultural ecosystems since domestication. Because of the large, repetitive genomes of these Triticeae crops, sequence information is limited and molecular differences between modern varieties are poorly understood. To study intraspecies genomic diversity, we compared large genomic sequences at the Lr34 locus of the wheat varieties Chinese Spring, Renan, and Glenlea, and diploid wheat Aegilops tauschii. Additionally, we compared the barley loci Vrs1 and Rym4 of the varieties Morex, Cebada Capa, and Haruna Nijo. Molecular dating showed that the wheat D genome haplotypes diverged only a few thousand years ago, while some barley and Ae. tauschii haplotypes diverged more than 500,000 years ago. This suggests gene flow from wild barley relatives after domestication, whereas this was rare or absent in the D genome of hexaploid wheat. In some segments, the compared haplotypes were very similar to each other, but for two varieties each at the Rym4 and Lr34 loci, sequence conservation showed a breakpoint that separates a highly conserved from a less conserved segment. We interpret this as recombination breakpoints of two ancient haplotypes, indicating that the Triticeae genomes are a heterogeneous and variable mosaic of haplotype fragments. Analysis of insertions and deletions showed that large events caused by transposable element insertions, illegitimate recombination, or unequal crossing over were relatively rare. Most insertions and deletions were small and caused by template slippage in short homopolymers of only a few base pairs in size. Such frequent polymorphisms could be exploited for future molecular marker development. 相似文献
96.
Aleksandra Rašić-Marković Olivera Stanojlović Dragan Hrnčić Danijela Krstić Mirjana Čolović Veselinka Šušić Tatjana Radosavljević Dragan Djuric 《Molecular and cellular biochemistry》2009,327(1-2):39-45
Hyperhomocysteinemia is associated with various pathologies including cardiovascular disease, stroke, and cognitive dysfunctions. Systemic administration of homocysteine can trigger seizures in animals, and patients with homocystinuria suffer from epileptic seizures. Available data suggest that homocysteine can be harmful to human cells because of its metabolic conversion to homocysteine thiolactone, a reactive thioester. A number of reports have demonstrated a reduction of Na+/K+-ATPase activity in cerebral ischemia, epilepsy and neurodegeneration possibly associated with excitotoxic mechanisms. The aim of this study was to examine the in vivo effects of d,l-homocysteine and d,l-homocysteine thiolactone on Na+/K+- and Mg2+-ATPase activities in erythrocyte (RBC), brain cortex, hippocampus, and brain stem of adult male rats. Our results demonstrate a moderate inhibition of rat hippocampal Na+/K+-ATPase activity by d,l-homocysteine, which however expressed no effect on the activity of this enzyme in the cortex and brain stem. In contrast,d,l-homocysteine thiolactone strongly inhibited Na+/K+-ATPase activity in cortex, hippocampus and brain stem of rats. RBC Na+/K+-ATPase and Mg2+-ATPase activities were not affected by d,l-homocysteine, while d,l-homocysteine thiolactone inhibited only Na+/K+-ATPase activity. This study results show that homocysteine thiolactone significantly inhibits Na+/K+-ATPase activity in the cortex, hippocampus, and brain stem, which may contribute at least in part to the understanding of excitotoxic and convulsive properties of this substance. 相似文献
97.
Tatjana Mihajilov-Krstev Dragan Radnović Dušanka Kitić Bojan Zlatković Mihailo Ristić Suzana Branković 《Central European Journal of Biology》2009,4(3):411-416
Essential oil of Satureja hortensis L. was analyzed by GC and GC/MS and tested by a broth micro-well dilution method for activity against multiresistant clinical
isolates of pathogenic bacteria from 10 different genera: Klebsiella, Escherichia, Proteus, Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Enterobacter, Citrobacter and Acinetobacter. The main compounds in the oil were carvacrol (67%), γ-terpinene (15.3%) and p-cymene (6.73%). The oil showed activity against
all tested strains. MIC/MBC values were in the range of 0.78-25 μl/ml, with the exception of the strain P. aeruginosa. Microbicidal
concentration for this particular strain (50 μl/ml) was the highest tested concentration. The oil showed inhibitory and bactericidal
effect at the same concentration (MIC=MBC) for all but three strains. 相似文献
98.
Dragan Perovic Jutta Förster Pierre Devaux Djabbar Hariri Morgane Guilleroux Kostya Kanyuka Rebecca Lyons Jens Weyen David Feuerhelm Ute Kastirr Pierre Sourdille Marion Röder Frank Ordon 《Molecular breeding : new strategies in plant improvement》2009,23(4):641-653
Monogenically-inherited resistance to Soil-borne cereal mosaic virus (SBCMV) in hexaploid bread wheat cultivars ‘Tremie’ and ‘Claire’ was mapped on chromosome 5D. The two closest flanking markers
identified in the Claire-derived mapping population, Xgwm469-5D and E37M49, are linked to the resistance locus at distances of 1 and 9 cm, respectively. Xgwm469-5D co-segregated with the SBCMV resistance in the Tremie-derived population and with the recently identified Sbm1 locus in the cv. Cadenza. This suggested that Tremie and Claire carry a resistance gene allelic to Sbm1, or one closely linked to it. The diagnostic value of Xgwm469-5D was assessed using a collection of SBCMV resistant and susceptible cultivars. Importantly, all susceptible genotypes carried
a null allele of Xgwm469-5D, whereas resistant genotypes presumably related to either Claire and Tremie or Cadenza revealed a 152 or 154 bp allele of
Xgwm469-5D, respectively. Therefore, Xgwm469-5D is well suited for marker assisted selection for SBCMV resistance. 相似文献
99.
Dragan AI Casas-Finet JR Bishop ES Strouse RJ Schenerman MA Geddes CD 《Biophysical journal》2010,99(9):3010-3019
PicoGreen is a fluorescent probe that binds dsDNA and forms a highly luminescent complex when compared to the free dye in solution. This unique probe is widely used in DNA quantitation assays but has limited application in biophysical analysis of DNA and DNA-protein systems due to limited knowledge pertaining to its physical properties and characteristics of DNA binding. Here we have investigated PicoGreen binding to DNA to reveal the origin and mode of PicoGreen/DNA interactions, in particular the role of electrostatic and nonelectrostatic interactions in formation of the complex, as well as demonstrating minor groove binding specificity. Analysis of the fluorescence properties of free PicoGreen, the diffusion properties of PG/DNA complexes, and the excited-state lifetime changes upon DNA binding and change in solvent polarity, as well as the viscosity, reveal that quenching of PicoGreen in the free state results from its intramolecular dynamic fluctuations. On binding to DNA, intercalation and electrostatic interactions immobilize the dye molecule, resulting in a >1000-fold enhancement in its fluorescence. Based on the results of this study, a model of PicoGreen/DNA complex formation is proposed. 相似文献
100.
S. Zdravković-Korać J. Milojević Lj. Tubić D. Ćalić-Dragosavac N. Mitić B. Vinterhalter 《Plant Cell, Tissue and Organ Culture》2010,101(2):237-244
A protocol has been developed for somatic embryogenesis and subsequent plant regeneration in Allium schoenoprasum L. Calli were induced from root sections isolated from axenic seedlings and cultivated on media containing either Murashige
and Skoog’s (MS) or Dunstan and Short’s mineral solution supplemented with 5 μM 2,4-dichlorophenoxyacetic acid (2,4-D) in
combination with 6-benzylaminopurine (BA), 6-furfurylaminopurine (Kin) or thidiazuron (TDZ) at 1, 5 or 10 μM. The highest
frequencies of callus induction were achieved on media with 5 μM 2,4-D in combination with 5 μM TDZ or 10 μM BA (78.9% and
78.4%, respectively). Calli were then transferred to 1 μM 2,4-D, where compact yellow callus turned to segmented yellowish
callus with transparent globular somatic embryos at the surface. Calli that were previously grown on media with 5 μM 2,4-D
in combination with 10 μM BA or 10 μM TDZ showed the highest frequencies of embryogenic callus formation (45% and 42%) as
well as mean number of somatic embryos per regenerating callus. The choice of mineral solution formulation did not significantly
affect callus induction or embryogenic callus formation. The embryos could complete development into whole plants on plant
growth regulator (PGR)-free medium, but inclusion of Kin (0.5, 2.5 and 5 μM) in this phase improved somatic embryo development
and multiplication. Subsequently transferred to 1/2 MS PGR-free medium, all embryos rooted and the survival rate of the plants
in a greenhouse was 96%. 相似文献