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101.
The biological function of chaperone complexes is to assist the folding of non-native proteins. The widely studied GroEL chaperonin is a double-barreled complex that can trap non-native proteins in one of its two barrels. The ATP-driven binding of a GroES cap then results in a major structural change of the chamber where the substrate is trapped and initiates a refolding attempt. The two barrels operate anti-synchronously. The central region between the two barrels contains a high concentration of disordered protein chains, the role of which was thus far unclear. In this work we report a combination of atomistic and coarse-grained simulations that probe the structure and dynamics of the equatorial region of the GroEL/GroES chaperonin complex. Surprisingly, our simulations show that the equatorial region provides a translocation channel that will block the passage of folded proteins but allows the passage of secondary units with the diameter of an alpha-helix. We compute the free-energy barrier that has to be overcome during translocation and find that it can easily be crossed under the influence of thermal fluctuations. Hence, strongly non-native proteins can be squeezed like toothpaste from one barrel to the next where they will refold. Proteins that are already fairly close to the native state will not translocate but can refold in the chamber where they were trapped. Several experimental results are compatible with this scenario, and in the case of the experiments of Martin and Hartl, intra chaperonin translocation could explain why under physiological crowding conditions the chaperonin does not release the substrate protein. 相似文献
102.
103.
Rodríguez-Argüelles MC Tourón-Touceda P Cao R García-Deibe AM Pelagatti P Pelizzi C Zani F 《Journal of inorganic biochemistry》2009,103(1):35-42
Cobalt, nickel, copper and zinc coordination compounds of two thiosemicarbazones with general composition ML2 (L: monodeprotonated ligand corresponding to 2-acetyl-γ-butyrolactone thiosemicarbazone, HL1, and 2-furancarbaldehyde thiosemicarbazone, HL2) and also complexes with general composition MCl2(HL2) were synthesized (except [NiCl2(HL2)] and [Co(L2)2]). The interaction of CuCl2 with HL2 gave [CuCl(HL2)], a copper(I) complex. The ligands and metal complexes were characterized by IR, 1H and 13C NMR spectroscopy, and magnetic susceptibility measurements. The crystal structure of [Ni(L2)2] · 2dmso was determined and a trans-square planar coordination of the two κ2-N,S chelate rings forming polymeric strips through H-bonds with dmso was observed. Actually, in all the reported complexes both ligands behaved as κ2-N,S chelates, except in the case of [Co(L1)2] in which HL1 is tridentate κ3-N,S,O. The antimicrobial properties of all compounds were studied using a wide spectrum of bacterial and fungal strains. The copper complexes of HL2 were the most active against all strains, including dermatophytes and phytopathogenic fungi. Most of the studied compounds, especially [Cu(L1)2], presented good activity against Haemophilus influenzae, a very harmful bacterium to humans. 相似文献
104.
Gianni Balliano Henrietta Dehmlow Simonetta Oliaro-Bosso Matilde Scaldaferri Silvia Taramino Franca Viola Giulia Caron Johannes Aebi Jean Ackermann 《Bioorganic & medicinal chemistry letters》2009,19(3):718-723
A series of 25 compounds, some of which previously were described as inhibitors of human liver microsomal oxidosqualene cyclase (OSC), were tested as inhibitors of Saccharomyces cerevisiae, Trypanosoma cruzi, Pneumocystis carinii and Arabidopsis thaliana OSCs expressed in an OSC-defective strain of S. cerevisiae. The screening identified three derivatives particularly promising for the development of novel anti-Trypanosoma agents and eight derivatives for the development of novel anti-Pneumocystis agents. 相似文献
105.
Mark R. Silvis Carol A. Bertrand Nadia Ameen Franca Golin-Bisello Michael B. Butterworth Raymond A. Frizzell Neil A. Bradbury 《Molecular biology of the cell》2009,20(8):2337-2350
The cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP/PKA-activated anion channel, undergoes efficient apical recycling in polarized epithelia. The regulatory mechanisms underlying CFTR recycling are understood poorly, yet this process is required for proper channel copy number at the apical membrane, and it is defective in the common CFTR mutant, ΔF508. Herein, we investigated the function of Rab11 isoforms in regulating CFTR trafficking in T84 cells, a colonic epithelial line that expresses CFTR endogenously. Western blotting of immunoisolated Rab11a or Rab11b vesicles revealed localization of endogenous CFTR within both compartments. CFTR function assays performed on T84 cells expressing the Rab11a or Rab11b GDP-locked S25N mutants demonstrated that only the Rab11b mutant inhibited 80% of the cAMP-activated halide efflux and that only the constitutively active Rab11b-Q70L increased the rate constant for stimulated halide efflux. Similarly, RNAi knockdown of Rab11b, but not Rab11a, reduced by 50% the CFTR-mediated anion conductance response. In polarized T84 monolayers, adenoviral expression of Rab11b-S25N resulted in a 70% inhibition of forskolin-stimulated transepithelial anion secretion and a 50% decrease in apical membrane CFTR as assessed by cell surface biotinylation. Biotin protection assays revealed a robust inhibition of CFTR recycling in polarized T84 cells expressing Rab11b-S25N, demonstrating the selective requirement for the Rab11b isoform. This is the first report detailing apical CFTR recycling in a native expression system and to demonstrate that Rab11b regulates apical recycling in polarized epithelial cells. 相似文献
106.
Oliaro-Bosso S Taramino S Viola F Tagliapietra S Ermondi G Cravotto G Balliano G 《Journal of enzyme inhibition and medicinal chemistry》2009,24(2):589-598
Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities. 相似文献
107.
108.
Alessandra Corradetti Franca Saccucci Monica Emanuelli Giorgia Vagnoni Monia Cecati Davide Sartini Stefano R. Giannubilo Andrea L. Tranquilli 《Cell stress & chaperones》2010,15(1):95-100
Mitogen-activated protein kinase (MAPK) p38α was shown to be implicated in the organogenesis of the placenta, and such placental
alteration is crucial for the development of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. We aimed
to analyze for the first time human placental expression of MAPK p38α in pregnancies complicated by HELLP. The placental expression
of MAPK p38α was investigated by semiquantitative polymerase chain reaction using cDNA extracted from placental tissue of
15 pregnancies with HELLP syndrome and 15 gestational age-matched controls. Seven patients with HELLP also had intrauterine
fetal growth restriction (IUGR). In placenta from pregnancy complicated by HELLP, the expression of MAPK p38α is significantly
decreased compared to the group with normal pregnancy (p < 0.001), while no difference was found between the HELLP and HELLP with IUGR subpopulations. Our study shows for the first
time that MAPK p38α is expressed in the human placenta. Pregnancies with placental dysfunction and hypertensive complications
are characterized by a significantly decreased expression of MAPK p38α. Our observations suggest that p38 MAPK signaling may
be essential in placental angiogenesis and functioning. 相似文献
109.
Effects of storage temperature on viability, germination and antioxidant metabolism in Ginkgo biloba L. seeds. 总被引:1,自引:0,他引:1
Franca Tommasi Costantino Paciolla Maria Concetta de Pinto Laura De Gara 《Plant Physiology and Biochemistry》2006,44(5-6):359-368
The behaviour of the Ginkgo biloba L. seeds was studied during storage at 4 and 25 degrees C. When stored at 25 degrees C, all the seeds died in 6 months. Cold temperatures preserved seed tissue viability for 1 year but did not preserve their capability to germinate, since such capability decreased after 6 months. A significant increase in lipid peroxidation occurred in the seed both in the embryo and in the endosperm. During storage a progressive deterioration of the endosperm tissues was evident. The two major water soluble antioxidants, ascorbate (ASC) and glutathione (GSH), showed different behaviour in the two conditions of storage and in the two main structures of the seed, the embryo and the endosperm. The ASC content of embryos and endosperms remained quite unchanged in the first 9 months at 4 degrees C, then increased. At 25 degrees C a significant decrease in the ASC content in the embryos was evident, whereas it remained more stable in the endosperm. The GSH pool decreased at both storage temperatures in the embryos. As far as the ASC-GSH redox enzymes are concerned, their activities decreased with storage, but changes appeared to be time-dependent more than temperature-dependent, with the exception of the endosperm ascorbate free radical (AFR) reductase (EC 1.6.5.4), the activity of which rapidly decreased at 25 degrees C. Therefore overall the antioxidant enzymes were scarcely regulated and unable to counteract oxidative stress occurring during the long-term storage. 相似文献
110.
Marino F Guasti L Cosentino M De Piazza D Simoni C Piantanida E Cimpanelli M Klersy C Bartalena L Venco A Lecchini S 《Life sciences》2006,78(10):1071-1077
Migration and superoxide anion (O2-) generation were studied in polymorphonuclear leukocytes (PMNs) from 14 athyreotic patients, previously treated by total thyroidectomy and radioiodine therapy for differentiated thyroid carcinoma, and from age- and sex-matched euthyroid healthy controls. Patients were studied twice: in hypothyroidism (visit 1) and after TSH-suppressive L-T4 replacement therapy (visit 2). Random migration and N-formyl-Met-Leu-Phe (fMLP) 0.1-microM induced chemotaxis were similar in cells from patients at both visit 1 and visit 2 and from healthy controls. On the contrary, resting O2- generation in cells from patients was significantly lower than control values, both at visit 1 and 2. At visit 1, fMLP 0.1 muM-induced O2- generation was significantly lower than control values, while phorbol-myristate acetate (PMA) 100-ng/ml induced O2- generation was similar in cells from patients and from controls. At visit 2 both responses increased, resulting in fMLP-induced O2- generation superimposable to control values and PMA-induced O2- generation significantly higher with respect to both visit 1 and cells from controls. In vitro exposure of PMNs from healthy subjects to L-T4 did not affect O2- generation in resting cells, and significantly increased that induced by fMLP or PMA only at high, supra-physiological concentrations. Neither TSH nor T3 had significant effects at any of the concentrations tested. The present results document the existence of a correlation between thyroid status and oxidative metabolism of human PMNs, which is however unlikely to depend upon a direct action of thyroid hormones on these cells. 相似文献