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991.
Extensive trypsinization of Na,K-ATPase from the salt gland of Squalus acanthias removes about half of the extramembranous protein mass of the alpha-subunit, while leaving the beta-subunit intact. Sequence analysis and epitope recognition of the remaining alpha-peptides show that transmembrane segments M1/M2 and M3/M4 are present when trypsinization is performed in either NaCl or RbCl. The M5/M6 segment and the intact 19-kDa peptide (M7-M10) are detected in Rb-trypsinized membranes but not in Na-trypsinized membranes. The L7/L8 loop is associated with Na-trypsinized membranes, indicating the presence of an M7/M8 or M8/M9 fragment. Freeze-fracture electron microscopy of both Rb- and Na-trypsinized membranes reveals intramembranous particles that indicate a retained cluster of peptides, even in the absence of an intact 19-kDa fragment. The rotational diffusion of covalently spin-labeled trypsinized complexes is studied in the presence of poly(ethylene glycol) or glycerol by using saturation transfer electron spin resonance. Rotational correlation times in aqueous poly(ethylene glycol) are longer than in glycerol solutions of the same viscosity and increase nonlinearly with the viscosity of the suspending medium, indicating that poly(ethylene glycol) induces aggregation of the tryptic peptides (and beta-subunit) within the membrane. The aggregates of enzyme trypsinized in the presence of NaCl are larger than those for enzyme trypsinized in RbCl, at both low and high aqueous viscosities. Similarities in mobility for native and Rb-trypsinized enzymes suggest either a change in average orientation of the spin-label upon trypsinization or that trypsinization leads to a reorganized protein structure that is more prone to aggregation. 相似文献
992.
Davidson SM Yellon DM 《American journal of physiology. Heart and circulatory physiology》2006,291(3):H1486; author reply H1487
993.
Lim WG Tan BJ Zhu Y Zhou S Armstrong JS Li QT Dong Q Chan E Smith D Verma C Tan SL Duan W 《Cellular signalling》2006,18(9):1473-1481
PRK1 is a lipid- and Rho GTPase-activated serine/threonine protein kinase implicated in the regulation of receptor trafficking, cytoskeletal dynamics and tumorigenesis. Although Rho binding has been mapped to the HR1 region in the regulatory domain of PRK1, the mechanism involved in the control of PRK1 activation following Rho binding is poorly understood. We now provide the first evidence that the very C-terminus beyond the hydrophobic motif in PRK1 is essential for the activation of this kinase by RhoA. Deletion of the HR1 region did not completely abolish the binding of PRK1-DeltaHR1 to GTPgammaS-RhoA nor the activation of this mutant by GTPgammaS-RhoA in vitro. In contrast, removing of the last six amino acid residues from the C-terminus of PRK1 or truncating of a single C-terminal residue from PRK1-DeltaHR1 completely abrogated the activation of these mutants by RhoA both in vitro and in vivo. The critical dependence of the very C-terminus of PRK1 on the signaling downstream of RhoA was further demonstrated by the failure of the PRK1 mutant lacking its six C-terminal residues to augment lisophosphatidic acid-elicited neurite retraction in neuronal cells. Thus, we show that the HR1 region is necessary but not sufficient in eliciting a full activation of PRK1 upon binding of RhoA. Instead, such activation is controlled by the very C-terminus of PRK1. Our results also suggest that the very C-terminus of PRK1, which is the least conserved among members of the protein kinase C superfamily, is a potential drug target for pharmacological intervention of RhoA-mediated signaling pathways. 相似文献
994.
Ana Maria Rodriguez de Ledesma Aarti N. Desai Valerie J. Bolivar Derek J. Symula Lorraine Flaherty 《Mammalian genome》2006,17(2):111-118
By use of newly developed subcongenic strains of mice from a parental B6.129-Il10−/− knockout/congenic strain, we have narrowed the critical region for a new behavioral QTL, called Emo4, for open-field activity to a segment of Chromosome 1 between Erbb4 (68.4Mb) and B3gnt7 (86.2 Mb). We have also uncovered an additional QTL governing repetitive beam breaks in the open field. This QTL, called
Reb1, maps to the interval between Asb1 (91.4 Mb) and NM_172851 (100.0 Mb) and is one of the first QTLs mapped for this type of behavior. Genome-wide microarray
expression analyses were then undertaken to help to identify candidate genes that may be the cause of these genetic differences
in open-field performance. In this effort, we analyzed global gene expression differences in the amygdalae by use of Affymetrix
GeneChips between B6, B6.129-Il10−/−, and B6.129R4. Several probe sets representing target Chr 1 genes were found that showed significantly differential expression
in the subcongenic and congenic strains. Several candidate genes have been identified. One of these regions coincides with
an homologous region in humans that has been associated with autism, a disease whose symptoms include repetitive actions.
This study illustrates that the use of congenic strains combined with global gene expression analyses can produce a list of
viable candidates. It further shows that caution should be observed when analyzing the effects of knockout/congenic strains
because many of the gene expression differences in these comparisons could not be attributable to the ablated Il10 gene but rather to passenger gene effects. 相似文献
995.
Jerzy M. Behnke Fuad A. Iraqi John M. Mugambi Simon Clifford Sonal Nagda Derek Wakelin Stephen J. Kemp R. Leyden Baker John P. Gibson 《Mammalian genome》2006,17(6):584-597
Fine mapping of quantitative trait loci (QTL) associated with resistance to the gastrointestinal parasite Heligmosomoides polygyrus was achieved on F6/F7 offspring (1076 mice) from resistant (SWR) and susceptible (CBA) mouse strains by selective genotyping (top and bottom 20%
selected on total worm count in week 6). Fecal egg counts were recorded at weeks 2, 4, and 6, and the average was also analyzed.
Blood packed cell volume in weeks 3 and 6 and five immunological traits (mucosal mast cell protease 1, granuloma score, IgG1
against adult worm, IgG1, and IgE to L4 antigen) were also recorded. On Chromosome 1 single-trait analyses identified a QTL
with effects on eight traits located at about 24 cM on the F2 mouse genome database (MGD) linkage map, with a 95% confidence interval (CI) of 20-32 cM established from a multitrait analysis.
On Chromosome 17 a QTL with effects on nine traits was located at about 18 cM on the MGD map (CI 17.9-18.4 cM). Strong candidate
genes for the QTL position on Chromosome 1 include genes known to be involved in regulating immune responses and on Chromosome
17 genes within the MHC, notably the Class II molecules and tumor necrosis factor. 相似文献
996.
Price DA Armour D de Groot M Leishman D Napier C Perros M Stammen BL Wood A 《Bioorganic & medicinal chemistry letters》2006,16(17):4633-4637
The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects. 相似文献
997.
Páli T Bashtovyy D Marsh D 《Protein science : a publication of the Protein Society》2006,15(5):1153-1161
The stoichiometry of the first shell of lipids interacting with a transmembrane protein is defined operationally by the population of spin-labeled lipid chains whose motion is restricted directly by the protein. Interaction stoichiometries have been determined experimentally for a wide range of alpha-helical integral membrane proteins by using spin-label ESR spectroscopy. Here, we determine the spatially defined number of first-shell lipids at the hydrophobic perimeter of integral membrane proteins whose 3D structure has been determined by X-ray crystallography and lipid-protein interactions characterized by spin-labeling. Molecular modeling is used to build a single shell of lipids surrounding transmembrane structures derived from the PDB. Constrained energy optimization of the protein-lipid assemblies is performed by molecular mechanics. For relatively small proteins (up to 7-12 transmembrane helices), the geometrical first shell corresponds to that defined experimentally by perturbation of the lipid-chain dynamics. For larger, multi-subunit alpha-helical proteins, the lipids perturbed directly by the protein may either exceed or be less in number than those that can be accommodated at the intramembranous perimeter. In these latter cases, the motionally restricted spin-labeled lipids can be augmented by intercalation, or can correspond to a specific subpopulation at the protein interface, respectively. For monomeric beta-barrel proteins, the geometrical lipid stoichiometry corresponds to that determined from lipid mobility for a 22-stranded barrel, but fewer lipids are motionally restricted than can be accommodated around an eight-stranded barrel. Deviations from the geometrical first shell, in the beta-barrel case, are for the smaller protein with a highly curved barrel. 相似文献
998.
Fujisaki W Koene A Arnold D Johnston A Nishida S 《Proceedings. Biological sciences / The Royal Society》2006,273(1588):865-874
We examined whether the detection of audio-visual temporal synchrony is determined by a pre-attentive parallel process, or by an attentive serial process using a visual search paradigm. We found that detection of a visual target that changed in synchrony with an auditory stimulus was gradually impaired as the number of unsynchronized visual distractors increased (experiment 1), whereas synchrony discrimination of an attended target in a pre-cued location was unaffected by the presence of distractors (experiment 2). The effect of distractors cannot be ascribed to reduced target visibility nor can the increase in false alarm rates be predicted by a noisy parallel processing model. Reaction times for target detection increased linearly with number of distractors, with the slope being about twice as steep for target-absent trials as for target-present trials (experiment 3). Similar results were obtained regardless of whether the audio-visual stimulus consisted of visual flashes synchronized with amplitude-modulated pips, or of visual rotations synchronized with frequency-modulated up-down sweeps. All of the results indicate that audio-visual perceptual synchrony is judged by a serial process and are consistent with the suggestion that audio-visual temporal synchrony is detected by a 'mid-level' feature matching process. 相似文献
999.
Quantitative genetic analysis of biomass and wood chemistry of Populus under different nitrogen levels 总被引:2,自引:1,他引:1
1000.
Löb S Königsrainer A Zieker D Brücher BL Rammensee HG Opelz G Terness P 《Cancer immunology, immunotherapy : CII》2009,58(1):153-157
Objectives Indoleamine-2,3-Dioxygenase (IDO) is an immunosuppressive molecule inducible in various cells. In addition to classic IDO
(IDO1), a new variant, IDO2, has recently been described. When expressed in dendritic cells (DCs) or cancer cells, IDO was
thought to suppress the immune response to tumors. A novel therapeutic approach in cancer envisages inhibition of IDO with
1-methyl-tryptophan (1MT). The levo-isoform (l-1MT) blocks IDO1, whereas dextro-1MT (d-1MT), which is used in clinical trials, inhibits IDO2. Here we analyze IDO2 expression in human cancer cells and the impact
of both 1-MT isoforms on IDO activity.
Methods Surgically extirpated human primary tumors as well as human cancer cell lines were tested for IDO1 and IDO2 expression by
RT-PCR. IDO1 activity of Hela cells was blocked by transfection with IDO1-specific siRNA and analysed for tryptophan degradation
by RP-HPLC. The impact of d-1MT and l-1MT on IDO activity of Hela cells and protein isolates of human colon cancer were studied.
Results Human primary gastric, colon and renal cell carcinomas constitutively expressed both, IDO1 and IDO2 mRNA, whereas cancer cells
lines had to be induced to by Interferon-gamma (IFN-γ). Treatment of Hela cells with IDO1-specific siRNA resulted in complete
abrogation of tryptophan degradation. Only l-1MT, and not d-1MT, was able to block IDO activity in IFN-γ-treated Hela cells as well as in protein isolates of primary human colon cancer.
Conclusions Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, d-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of d-1MT, this cannot be attributed to inhibition of IDO in tumor cells. 相似文献