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991.
Structural domains involved in substrate selectivity in two neutral amino acid transporters 总被引:1,自引:0,他引:1
Soragna A Mari SA Pisani R Peres A Castagna M Sacchi VF Bossi E 《American journal of physiology. Cell physiology》2004,287(3):C754-C761
The ability of the two highly homologous Na+/Cl-dependent neutral amino acid transporters KAAT1 and CAATCH1, cloned from the midgut epithelium of the larva Manduca sexta, to transport different amino acids depends on the cotransported ion, on pH, and on the membrane voltage. Different organic substrates give rise to transport-associated currents with their own characteristics, which are notably distinct between the two proteins. Differences in amplitude, kinetics, and voltage dependence of the transport-associated currents have been observed, as well as different substrate selectivity patterns measured by radioactive amino acid uptake assays. These diversities represent useful tools to investigate the structural determinants involved in the substrate selectivity. To identify these regions, we built four chimeric proteins between the two transporters. These proteins, heterologously expressed in Xenopus laevis oocytes, were analyzed by two-electrode voltage clamp and uptake measurements. Initially, we exchanged the first three domains, obtaining the chimeras C3K9 and K3C9 (where numbers indicate the transmembrane domains and letters represent the original proteins), which showed electrophysiological and [3H]amino acid uptake characteristics resembling those of KAAT1 and CAATCH1, respectively. Subsequent substitution of the last four domains in C3K9 and K3C9 gave the proteins C3K5C4 and K3C5K4, which showed the same behavior as KAAT1 and CAATCH1 in electrophysiological and transport determinations. These results suggest that in KAAT1 and CAATCH1, only the central transmembrane domains (from 4 to 8) of the protein are responsible for substrate selectivity. structure and function; Manduca sexta 相似文献
992.
Nardini M Mazzocco M Massaro A Maffei M Vergano A Donadini A Scartezzini P Bolognesi M 《Biochemical and biophysical research communications》2004,318(2):470-476
We report the 1.6 Angstrom resolution crystal structure of SH3BGRL3, a member of a new mammalian protein family of unknown function. The observed "thioredoxin fold" of SH3BGRL3 matches the tertiary structure of glutaredoxins, even in the N-terminal region where the sequence similarity between the two protein families is negligible. In particular, SH3BGRL3 displays structural modifications at the N-terminal Cys-x-x-Cys loop, responsible for glutathione binding and catalysis in glutaredoxins. The loop hosts a six residue insertion, yielding an extra N-terminal-capped helical turn, first observed here for the thioredoxin fold. This, together with deletion of both Cys residues, results in a substantial reshaping of the neighboring cleft, where glutathione is hosted in glutaredoxins. While not active in redox reaction and glutathione binding, SH3BGRL3 may act as an endogenous modulator of glutaredoxin activities by competing, with its fully conserved thioredoxin fold, for binding to yet unknown target proteins. 相似文献
993.
SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization 总被引:7,自引:0,他引:7
Verderio C Pozzi D Pravettoni E Inverardi F Schenk U Coco S Proux-Gillardeaux V Galli T Rossetto O Frassoni C Matteoli M 《Neuron》2004,41(4):599-610
SNAP-25 is a component of the SNARE complex implicated in synaptic vesicle exocytosis. In this study, we demonstrate that hippocampal GABAergic synapses, both in culture and in brain, lack SNAP-25 and are resistant to the action of botulinum toxins type A and E, which cleave this SNARE protein. Relative to glutamatergic neurons, which express SNAP-25, GABAergic cells were characterized by a higher calcium responsiveness to depolarization. Exogenous expression of SNAP-25 in GABAergic interneurons lowered calcium responsiveness, and SNAP-25 silencing in glutamatergic neurons increased calcium elevations evoked by depolarization. Expression of SNAP-25(1-197) but not of SNAP-25(1-180) inhibited calcium responsiveness, pointing to the involvement of the 180-197 residues in the observed function. These data indicate that SNAP-25 is crucial for the regulation of intracellular calcium dynamics and, possibly, of network excitability. SNAP-25 is therefore a multifunctional protein that participates in exocytotic function both at the mechanistic and at the regulatory level. 相似文献
994.
995.
D'Isa G Galeone A Oliviero G Piccialli G Varra M Mayol L 《Bioorganic & medicinal chemistry letters》2004,14(21):5417-5421
The three oligodeoxyribonucleotides (ODNs) a-c, having the telomeric repeat d(TTAGGG)(4) sequence and incorporating gamma-hydroxypropano deoxyguanosine at different positions, were synthesized. Gel electrophoresis and CD analyses indicated that the ODNs assume monomolecular quadruplex structures in Na+ and in K+ buffers. The T(m) values, obtained by CD melting experiments, showed that the presence of the acrolein-dG adduct into the ODN b decreases the thermal stability of the monomolecular quadruplex structure in Na+ solution, whereas for a and c no significant effect could be detected in the same experimental conditions. On the contrary, all ODNs a-d show the same behaviour in K+ buffer. These findings are briefly discussed. 相似文献
996.
Franchetti P Pasqualini M Petrelli R Ricciutelli M Vita P Cappellacci L 《Bioorganic & medicinal chemistry letters》2004,14(18):4655-4658
The beta-anomers of N-ribofuranosylnicotine-3-carboxamide (beta-NAR) and its nicotinic acid analog (beta-NaR) were obtained by stereoselective synthesis via glycosylation of the presilylated bases under Vorbruggen's protocol. A NAR analog, methylated in position 3 of the ribosylic moiety, is also reported. 相似文献
997.
Over the past decade, evidence has accumulated indicating that, during development, the construction of synapses--the sites of communication between neurons--might rely on the utilization of preassembled sets of synaptic proteins, which have already accumulated in the axon and are highly mobile, before getting recruited to the sites of contact with the postsynaptic neuron. In this review, we discuss evidence from most recent publications pointing to the existence of active vesicle traffic and turnover in developing neurons, which lead to the construction of new synaptic sites. 相似文献
998.
Guiotto A Canevari M Pozzobon M Moro S Orsolini P Veronese FM 《Bioorganic & medicinal chemistry》2004,12(19):5031-5037
Branched poly(ethylene glycols) (PEG2) are nowadays widely used for protein and peptides bioconjugation, for their favourable properties (such as the ability to protect the protein surface in an 'umbrella like' fashion). The discovery that mPEG(2)-LysMetbeta AlaOEt lost one mPEG chain during standard base-catalysed ester hydrolysis conditions prompted us to investigate the hydrolytic stability of such systems and the mechanism involved in the PEG chain loss. A series of branched PEGs, substituted with different aminoacids and dipeptides, have been prepared to test the influence of steric hindrance, chain lengths, ramification and Lys-AA amide substitution on hydrolysis. Unexpected results reveal an anchimeric assistance of the Lys-AaA amide proton to the hydrolysis of the carbamoyl moiety joining mPEG to the alpha-amino group of lysine through the formation of an hydantoin system. 相似文献
999.
Salmona M Morbin M Massignan T Colombo L Mazzoleni G Capobianco R Diomede L Thaler F Mollica L Musco G Kourie JJ Bugiani O Sharma D Inouye H Kirschner DA Forloni G Tagliavini F 《The Journal of biological chemistry》2003,278(48):48146-48153
Prion protein (PrP) amyloid formation is a central feature of genetic and acquired forms of prion disease such as Gerstmann-Str?ussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues approximately 82-146. To investigate the determinants of the physicochemical properties of this fragment, we synthesized PrP-(82-146) and variants thereof, including entirely and partially scrambled peptides. PrP-(82-146) readily formed aggregates that were partially resistant to protease digestion. Peptide assemblies consisted of 9.8-nm-diameter fibrils having a parallel cross-beta-structure. Second derivative of infrared spectra indicated that PrP-(82-146) aggregates are primarily composed of beta-sheet (54%) and turn (24%) which is consistent with their amyloid-like properties. The peptide induced a remarkable increase in plasma membrane microviscosity of primary neurons. Modification of the amino acid sequence 106-126 caused a striking increase in aggregation rate, with formation of large amount of protease-resistant amorphous material and relatively few amyloid fibrils. Alteration of the 127-146 region had even more profound effects, with the inability to generate amyloid fibrils. These data indicate that the intrinsic properties of PrP-(82-146) are dependent upon the integrity of the C-terminal region and account for the massive deposition of PrP amyloid in GSS. 相似文献
1000.