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Tjakko J. van Ham Alessandro Esposito Shang-Te D. Hsu Clemens F. Kaminski Ellen A.A. Nollen Carlos W. Bertoncini 《Journal of molecular biology》2010,395(3):627-12905
Misfolding and aggregation of proteins are characteristics of a range of increasingly prevalent neurodegenerative disorders including Alzheimer's and Parkinson's diseases. In Parkinson's disease and several closely related syndromes, the protein α-synuclein (AS) aggregates and forms amyloid-like deposits in specific regions of the brain. Fluorescence microscopy using fluorescent proteins, for instance the yellow fluorescent protein (YFP), is the method of choice to image molecular events such as protein aggregation in living organisms. The presence of a bulky fluorescent protein tag, however, may potentially affect significantly the properties of the protein of interest; for AS in particular, its relative small size and, as an intrinsically unfolded protein, its lack of defined secondary structure could challenge the usefulness of fluorescent-protein-based derivatives. Here, we subject a YFP fusion of AS to exhaustive studies in vitro designed to determine its potential as a means of probing amyloid formation in vivo. By employing a combination of biophysical and biochemical studies, we demonstrate that the conjugation of YFP does not significantly perturb the structure of AS in solution and find that the AS-YFP protein forms amyloid deposits in vitro that are essentially identical with those observed for wild-type AS, except that they are fluorescent. Of the several fluorescent properties of the YFP chimera that were assayed, we find that fluorescence anisotropy is a particularly useful parameter to follow the aggregation of AS-YFP, because of energy migration Förster resonance energy transfer (emFRET or homoFRET) between closely positioned YFP moieties occurring as a result of the high density of the fluorophore within the amyloid species. Fluorescence anisotropy imaging microscopy further demonstrates the ability of homoFRET to distinguish between soluble, pre-fibrillar aggregates and amyloid fibrils of AS-YFP. Our results validate the use of fluorescent protein chimeras of AS as representative models for studying protein aggregation and offer new opportunities for the investigation of amyloid aggregation in vivo using YFP-tagged proteins. 相似文献
95.
Scanning electron microscopic investigation of seed surfaces in tribe Hydrophylleae (Hydrophyllaceae) and seed development in Nemophila indicates the presence of four closely related genera (Ellisia, Hydrophyllum, Nemophila, Pholistoma) and one aberrant genus (Eucrypta), which should probably be transferred elsewhere. Comparative evidence from embryology, morphology, cytology, and palynology is roughly corroborative. 相似文献
96.
Oishi S Karki RG Shi ZD Worthy KM Bindu L Chertov O Esposito D Frank P Gillette WK Maderia M Hartley J Nicklaus MC Barchi JJ Fisher RJ Burke TR 《Bioorganic & medicinal chemistry》2005,13(7):2431-2438
Preferential binding of ligands to Grb2 SH2 domains in beta-bend conformations has made peptide cyclization a logical means of effecting affinity enhancement. This is based on the concept that constraint of open-chain sequences to bend geometries may reduce entropy penalties of binding. The current study extends this approach by undertaking ring-closing metathesis (RCM) macrocyclization between i and i+3 residues through a process involving allylglycines and beta-vinyl-functionalized residues. Ring closure in this fashion results in minimal macrocyclic tetrapeptide mimetics. The predominant effects of such macrocyclization on Grb2 SH2 domain binding affinity were increases in rates of association (from 7- to 16-fold) relative to an open-chain congener, while decreases in dissociation rates were less pronounced (approximately 2-fold). The significant increases in association rates were consistent with pre-ordering of solution conformations to near those required for binding. Data from NMR experiments and molecular modeling simulations were used to interpret the binding results. An understanding of the conformational consequences of such i to i+3 ring closure may facilitate its application to other systems where bend geometries are desired. 相似文献
97.
Evaluation of dietary practices of National Collegiate Athletic Association Division I football players 总被引:1,自引:0,他引:1
Cole CR Salvaterra GF Davis JE Borja ME Powell LM Dubbs EC Bordi PL 《Journal of strength and conditioning research / National Strength & Conditioning Association》2005,19(3):490-494
The objective of this study is to evaluate the dietary practices of 28 football athletes on a National Collegiate Athletic Association (NCAA) Division I team using 3-day diet records. Student athletes completed 3-day diet records at 2 individual points of time, when no training table was available. Diet records were evaluated and were compared with the Third National Health and Nutrition Survey (NHANES III) data for the same ages and gender group. No differences in dietary practices of collegiate football athletes were observed when compared with data for the same ages and gender group culled from NHANES III. Inadequacies in energy intake for activity level were significant (p < 0.05). Influences of fad dieting trends were noted when the diets were mapped onto the United States Department of Agriculture (USDA) food guide pyramid. Changes in diet would be necessary to sustain the activity level of these athletes. 相似文献
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Esposito V Randazzo A Virgilio A Cozzuto L Mayol L 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):783-788
The effects of incorporation of 8-oxoadenosine in two different truncations of human telomeric sequence forming quadruplex structures are reported. In order to characterise their structures, a combination of NMR and UV spectroscopy and computational techniques were used. Both oligonucleotides have been found to form fourfold symmetric quadruplex structures. As a tautomeric equilibrium between keto and enol forms of 8-oxoadenosine may establish in solution and intrinsic stabilities effects, such as internal H-bonds, for example, may determine the predominance of some particular tautomer, molecular modelling studies were performed on quadruplex structures containing both the tautomeric forms. Both molecules resulted to be thermally less stable than the natural. 相似文献
100.
Esposito V Randazzo A Petraccone L Giancola C Erra E Virgilio A Mayol L 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):789-794
Truncated sequences of human telomeric DNA can readily assemble to form parallel stranded quadruplexes containing A- and G-tetrads. The formation of an A-tetrad is highly context-dependent and the relationship between the formation of an A-tetrad and the glycosidic torsion angle of the adenosine residues implicated has not been completely clarified so far. In order to give a further insight in this issue we synthesized the modified oligomers d(ABrGGGT) and d(TABrGGGT), two different truncations of the human telomeric sequence containing a 8-bromoadenosine residue, named ABr. NMR data show that both the modified oligomers are able to perfectly fold into highly symmetric quadruplexes with all strands parallel to each other. Molecular modeling studies were performed on both [d(ABrGGGT)]4 and [d(TABrGGGT)]4, indicating that a bulky substituent, such as a bromine atom at the C8 position of adenines, can force the glycosidic bond to adopt a syn conformation, stabilizing the resulting quadruplexes. 相似文献