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91.
92.
Amir Shahmoradi Dariya K. Sydykova Stephanie J. Spielman Eleisha L. Jackson Eric T. Dawson Austin G. Meyer Claus O. Wilke 《Journal of molecular evolution》2014,79(3-4):130-142
Several recent works have shown that protein structure can predict site-specific evolutionary sequence variation. In particular, sites that are buried and/or have many contacts with other sites in a structure have been shown to evolve more slowly, on average, than surface sites with few contacts. Here, we present a comprehensive study of the extent to which numerous structural properties can predict sequence variation. The quantities we considered include buriedness (as measured by relative solvent accessibility), packing density (as measured by contact number), structural flexibility (as measured by B factors, root-mean-square fluctuations, and variation in dihedral angles), and variability in designed structures. We obtained structural flexibility measures both from molecular dynamics simulations performed on nine non-homologous viral protein structures and from variation in homologous variants of those proteins, where they were available. We obtained measures of variability in designed structures from flexible-backbone design in the Rosetta software. We found that most of the structural properties correlate with site variation in the majority of structures, though the correlations are generally weak (correlation coefficients of 0.1–0.4). Moreover, we found that buriedness and packing density were better predictors of evolutionary variation than structural flexibility. Finally, variability in designed structures was a weaker predictor of evolutionary variability than buriedness or packing density, but it was comparable in its predictive power to the best structural flexibility measures. We conclude that simple measures of buriedness and packing density are better predictors of evolutionary variation than the more complicated predictors obtained from dynamic simulations, ensembles of homologous structures, or computational protein design. 相似文献
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94.
J Spielman S R Hull Z Q Sheng R Kanterman A Bright K L Carraway 《The Journal of biological chemistry》1988,263(20):9621-9629
The major cell surface glycoprotein (ascites sialoglycoprotein-1 (ASGP-1] of ascites 13762 rat mammary tumor cells is a large (Mr greater than 500,000), highly glycosylated sialomucin which is present in great abundance (greater than 0.5% of total cell protein). Thus, these tumors provide a useful system for investigating the biosynthesis of O-glycosylated glycoproteins. Previous studies in this system have demonstrated that initiation of O-linked oligosaccharides occurs throughout most of the transit period of ASGP-1 from the endoplasmic reticulum to the cell surface. By pulse-chase threonine labeling and precipitation with peanut agglutinin, ASGP-1 is first observed as an immature lightly glycosylated form (Mr approximately 200,000) which is converted to a more mature, more heavily glycosylated form (designated the premature or P form) with a half-time of about 30 min. The P form is then more gradually converted into the mature ASGP-1. Analysis of glucosamine-labeled oligosaccharitols obtained from the immature form showed primarily unsialylated derivatives consisting of the structures of the size of the tetrasaccharide Gal beta 1,4GlcNAc beta 1,6(Gal beta 1,3)GalNAc and smaller, whereas the mature form showed a mixture of sialylated and unsialylated structures. Desialylation of glucosamine-labeled mature form resulted in a glycoprotein intermediate in size between the immature and mature forms, indicating that the size change with maturation is not solely due to sialylation. Treatment of the cells with 10(-6) M monensin significantly reduced the conversion of immature to mature form without inhibiting initiation of O-linked oligosaccharides and without preventing sialylation. Analysis of oligosaccharitols obtained from ASGP-1 of monensin-treated cells showed that the major oligosaccharides are trisaccharide GlcNAc beta 1,6(Gal beta 1,3)GalNAc and sialylated trisaccharide GlcNAc beta 1,6(NeuAc alpha 2,3-Gal-beta 1,3) GalNAc. These results suggest that monensin specifically disrupts the compartment of the biosynthetic pathway which adds most of the beta 1,4-Gal to the oligosaccharides of ASGP-1 and that this compartment is separate from the primary site of sialylation. 相似文献
95.
Cheung VG Bruzel A Burdick JT Morley M Devlin JL Spielman RS 《American journal of human genetics》2008,82(6):1357-1360
Variation in the level of gene expression is a major determinant of a cell's function and characteristics. Common allelic variants of genes can be expressed at different levels and thus contribute to phenotypic diversity. We have measured allelic expression differences at heterozygous loci in monozygotic twins and in unrelated individuals. We show that the extent of differential allelic expression is highly similar within monozygotic twin pairs for many loci, implying that allelic differences in gene expression are under genetic control. We also show that even subtle departures from equal allelic expression are often genetically determined. 相似文献
96.
Quantitative trait transmission/disequilibrium tests (quantitative TDTs) are commonly used in family-based genetic association studies of quantitative traits. Despite the availability of various quantitative TDTs, some users are not aware of the properties of these tests and the relationships between them. This review aims at outlining the broad features of the various quantitative TDT procedures carried out in the frequently used QTDT and FBAT packages. Specifically, we discuss the “Rabinowitz” and the “Monks-Kaplan” procedures, as well as the various “Abecasis” and “Allison” regression-based procedures. We focus on the models assumed in these tests and the relationships between them. Moreover, we discuss what hypotheses are tested by the various quantitative TDTs, what testing procedures are best suited to various forms of data, and whether the regression-based tests overcome population stratification problems. Finally, we comment on power considerations in the choice of the test to be used. We hope this brief review will shed light on the similarities and differences of the various quantitative TDTs. 相似文献
97.
Parameswaran Narayanan Spielman Wiliam S. Brooks David P. Nambi Ponnal 《Molecular and cellular biochemistry》2004,260(1):7-11
Glomerular mesangial cells play an important role in the development of glomerulosclerosis. Mesangial cell apoptosis has been shown to be involved in different stages of development of glomerulonephritis. The aim of the present study was to evaluate the effect of inhibition of serine/threonine phosphatases by okadaic acid, a shell fish toxin, on rat mesangial cell apoptosis and to examine the molecular mechanisms particularly the role of caspases. Okadaic acid significantly induced mesangial cell apoptosis, as measured by an increase in cytoplasmic nucleosome-associated DNA fragmentation. The induction of apoptosis was dependent on protein synthesis, because cyclohexamide, a protein synthesis inhibitor, blocked okadaic acid-induced apoptosis. In addition, okadaic acid stimulated caspase activities (as measured by caspase substrate peptide hydrolysis) in cultured rat mesangial cells at different time points. After 12 h treatment, okadaic acid caused a modest increase in caspase-8 (IETD-pNAse)(159.3 ± 6.7%) activity, while after 18 h treatment, okadaic acid caused a significant increase in caspase-3 (DEVD-pNAse)(906 ± 245%) activity. Okadaic acid-stimulated caspase-3 activity was inhibited by Z-IETD-FMK (caspase-8 inhibitor) suggesting that the caspase-3 activity is downstream of caspase-8 activity. Both caspase-3 and caspase-8 inhibitors blocked okadaic acid-stimulated apoptosis. These data suggest that inhibition of protein phosphatases by okadaic acid induces apoptosis in rat mesangial cells by activating caspase-3- and -8-like activities and that caspase-3-like activity is downstream of caspase-8-like activity. 相似文献
98.
Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families 总被引:20,自引:0,他引:20
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Cox NJ Wapelhorst B Morrison VA Johnson L Pinchuk L Spielman RS Todd JA Concannon P 《American journal of human genetics》2001,69(4):820-830
Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases. 相似文献
99.
Bitter taste transduced by PLC-beta(2)-dependent rise in IP(3) and alpha-gustducin-dependent fall in cyclic nucleotides 总被引:5,自引:0,他引:5
Yan W Sunavala G Rosenzweig S Dasso M Brand JG Spielman AI 《American journal of physiology. Cell physiology》2001,280(4):C742-C751
Current evidence points to the existence of multiple processesfor bitter taste transduction. Previous work demonstrated involvement of the polyphosphoinositide system and an -gustducin(Ggust)-mediated stimulation of phosphodiesterase inbitter taste transduction. Additionally, a taste-enriched G protein-subunit, G13, colocalizes with Ggustand mediates the denatonium-stimulated production of inositol1,4,5-trisphosphate (IP3). Using quench-flow techniques, weshow here that the bitter stimuli, denatonium and strychnine, inducerapid (50-100 ms) and transient reductions in cAMP and cGMP andincreases in IP3 in murine taste tissue. This decrease ofcyclic nucleotides is inhibited by Ggust antibodies,whereas the increase in IP3 is not affected by antibodiesto Ggust. IP3 production is inhibited byantibodies specific to phospholipase C-2(PLC-2), a PLC isoform known to be activated byG-subunits. Antibodies to PLC-3 or toPLC-4 were without effect. These data suggest atransduction mechanism for bitter taste involving the rapid andtransient metabolism of dual second messenger systems, both mediatedthrough a taste cell G protein, likely composed ofGgust//13, with both systems beingsimultaneously activated in the same bitter-sensitive taste receptor cell. 相似文献
100.