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71.
Effect of pathogenic cysteine mutations on FGFR3 transmembrane domain dimerization in detergents and lipid bilayers 总被引:2,自引:0,他引:2
Mutations in fibroblast growth factor receptors are known as the genetic basis of skeletal growth disorders. The mechanism of pathogenesis, as determined by mutation-induced changes in receptor structure, interactions, and function, is elusive. Here we study three pathogenic Cys mutations, associated with either thanatophoric dysplasia or achondroplasia, in the TM domain of fibroblast growth factor receptors 3 (FGFR3). We characterize the dimerization propensities of the mutant TM domains in detergents and in lipid bilayers, in the presence and absence of reducing agents, and compare them to previous measurements of wild-type. We find that the Cys mutations increase the propensity for dimerization in detergent, with the Cys370 mutant exhibiting the highest propensity for disulfide bond formation, the Cys371 mutant having an intermediate propensity, and Cys375 the lowest. Thus, disulfide bonds readily form in detergents, with efficiency that correlates with the severity of the phenotype. In lipid bilayers, however, the Cys370 mutant, which dimerizes strongly in detergent, behaves as the wild-type, suggesting that Cys370-mediated disulfide bonds do not form between the isolated TM domains in bilayers. Thus, the nature of the hydrophobic environment plays an important role in defining the structure and flexibility of transmembrane dimers. These results and previous findings from cellular studies lead us to propose a conformational flexibility mechanism of receptor stabilization as a basis for disregulated FGFR3 signaling in thanatophoric dysplasia and achondroplasia. 相似文献
72.
Naumova E Panchev P Simeonov PJ Mihaylova A Penkova K Boneva P Marinova D Paskalev E Simeonov PL Zlatev A 《Cell and tissue banking》2008,9(4):337-342
The transplantation program in Bulgaria started in 1968 with renal transplantations to a child and adult woman. In 1986 the
first heart transplantation was performed. To date a total of 10 heart transplants have been performed, including one combined
heart/lung. A liver transplantation program was launched in 2005 with a total number of 16 transplantations—7 from living
donors and 9 from deceased donors. The highest transplantation activity is registered in the field of renal transplantation.
During the period 1980–2006, 462 Bulgarian recipients of kidney were transplanted in Bulgaria. The ratio between transplantations
from deceased and living related donors is approximately 1:0.9. Annual transplantation activity varies among the years from
1 to 12 renal transplantations p.m.p./per year. The 1- (80.7% vs. 63.1%), 5- (57.86% vs. 39.0%) and 10-year (42.65% vs. 23.62%)
graft survival rates are higher for recipients of living donor kidneys compared to those of deceased donor. In 1983 a National
kidney waiting list was established. Currently the number of the registered patients eligible for renal transplantation is
885. The proportion of sensitized patients in the waiting list is 20.45% and 4.34% of them are hyperimmunized. Recently HLAMatchmaker
program has been implemented not only for sensitized patients but also for those with rare alleles and haplotypes. Post-transplant
immunological monitoring showed a strong association between alloantibody presence and delayed graft function (Chi-square = 10.73,
P < 0.001), acute rejection (Chi-square = 14.504, P < 0.001), chronic rejection (Chi-square = 12.84, P < 0.001) and graft loss (Chi-square = 20.283, P < 0.001). Based on the experience in our transplant center a strategy for improvement of long-term renal graft survival was
developed and implemented. 相似文献
73.
J. Mucksová J.P. Brillard J. Hejnar M. Poplštein J. Kalina M. Bakst H. Yan P. Trefil 《Animal reproduction science》2009
Precise identification of the male germinal stem cell population is important for their practical use in programs dedicated to the integration of exogenous genetic material in testicular tissues. In the present study, our aim was to identify germinal cell populations in the testes of pubertal and adult cockerels based on the detection of the nuclear DNA content by fluorescence-activated cell sorting (FACS) and on the expression of the Dazl and Stra8 genes in single-cell suspensions of testicular tissues. Cells with a tetraploid DNA content (4c) represent a small and equal fraction of the total germinal cell population in both pubertal and adult males. In contrast, the diploid (2c) and haploid (c) subpopulations differ significantly between ages as a consequence of different degrees of sexual maturation. A specific subpopulation of testicular cells, the side-scatter subpopulation of cells, or side population (SP), was identified at the junction between the haploid and diploid cell populations. The percentage of this cell subpopulation differs significantly in pubertal and adult cockerels, accounting for 4.1% and 1.3% of the total cell population, respectively. These four testicular cell populations were also tested for the expression of Dazl and Stra8 genes known to be expressed in premeiotic cells including stem spermatogonia. Both genes were expressed in SP, whereas the expression of either Dazl or Stra8 genes was detected only in the 4c and in the 2c testicular cell subpopulations, respectively. The correlation between the cell ploidy and Dazl/Stra8 expression was the same at both male ages. We conclude that SP cells might represent a subpopulation of germinal cells enriched in stem spermatogonia, which can be of great importance for transgenesis in chicken. 相似文献
74.
Mutations in the transmembrane (TM) domains of receptor tyrosine kinases (RTKs) have been implicated in the induction of pathological phenotypes. These mutations are believed to stabilize the RTK dimers, and thus promote unregulated signaling. However, the energetics behind the pathology induction has not been determined. An example of a TM domain pathogenic mutation is the Ala391-->Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer. Here, we determine the free energy of dimerization of wild-type and mutant FGFR3 TM domain in lipid bilayers using F?rster resonance energy transfer, and we show that hydrogen bonding between Glu391 and the adjacent helix in the dimer is a feasible mechanism for dimer stabilization. The measured change in the free energy of dimerization due to the Ala391-->Glu pathogenic mutation is -1.3 kcal/mol, consistent with previous reports of hydrogen bond strengths in proteins. This is the first quantitative measurement of mutant RTK stabilization in a membrane environment. We show that this seemingly modest value can lead to a large increase in dimer fraction and thus profoundly affect RTK-mediated signal transduction. 相似文献
75.
Receptor tyrosine kinase transmembrane domains: Function,dimer structure and dimerization energetics
The transmembrane (TM) domains of receptor tyrosine kinases (RTKs) play an active role in signaling. They contribute to the stability of full-length receptor dimers and to maintaining a signaling-competent dimeric receptor conformation. In an exciting new development, two structures of RTK TM domains have been solved, a break-through achievement in the field. Here we review these structures, and we discuss recent studies of RTK TM domain dimerization energetics, possible synergies between domains, and the effects of pathogenic RTK TM mutations on structure and dimerization.Key words: transmembrane domain, dimerization thermodynamics, receptor tyrosine kinases, pathogenic mutations, dimer structure 相似文献
76.
77.
Nina Stancheva Jost Weber Josef Schulze Kalina Alipieva Jutta Ludwig-Müller Christiane Haas Vasil Georgiev Thomas Bley Milen Georgiev 《Plant Cell, Tissue and Organ Culture》2011,105(1):79-84
A cell suspension culture of Devil’s claw (Harpagophytum procumbens), a South African plant with high medicinal value, cultivated under submerged conditions showed stable growth and accumulated
high amounts of biomass (18.2 g l−1). Flow cytometry analyses of the suspension’s cell cycle kinetics showed that proportions of cells in G0/G1 and S phases varied insignificantly (between 69–76% and 9–13%, respectively) during the cultivation, while the proportion
of G2/M-phase cells increased until day 8 of cultivation, when the exponential phase of cell growth ended. Metabolite production
in the culture was studied through simultaneous determination of three bioactive phenylethanoid glycosides (verbascoside,
β-OH-verbascoside and leucosceptoside A) by high performance liquid chromatography. It was found that suspended Devil’s claw
cells accumulated mainly verbascoside (517.3 mg l−1), followed by leucosceptoside A (107.1 mg l−1) and β-OH-verbascoside (80.3 mg l−1). In addition, several fatty acids and β-sitosterol were identified in the cell suspension by gas chromatographic-mass spectrometry
analysis. Comparison of the results with previously acquired data for Harpagophytum procumbens transformed roots indicate that cell suspensions cultures are more promising as potential commercial sources of metabolites
such as phenylethanoid glycosides. 相似文献
78.
79.
Milan Kuchař Lucie Vaňková Hana Petroková Jiří Černý Radim Osička Ondřej Pelák Hana Šípová Bohdan Schneider Jiří Homola Peter Šebo Tomáš Kalina Petr Malý 《Proteins》2014,82(6):975-989
Engineered combinatorial libraries derived from small protein scaffolds represent a powerful tool for generating novel binders with high affinity, required specificity and designed inhibitory function. This work was aimed to generate a collection of recombinant binders of human interleukin‐23 receptor (IL‐23R), which is a key element of proinflammatory IL‐23‐mediated signaling. A library of variants derived from the three‐helix bundle scaffold of the albumin‐binding domain (ABD) of streptococcal protein G and ribosome display were used to select for high‐affinity binders of recombinant extracellular IL‐23R. A collection of 34 IL‐23R‐binding proteins (called REX binders), corresponding to 18 different sequence variants, was used to identify a group of ligands that inhibited binding of the recombinant p19 subunit of IL‐23, or the biologically active human IL‐23 cytokine, to the recombinant IL‐23R or soluble IL‐23R‐IgG chimera. The strongest competitors for IL‐23R binding in ELISA were confirmed to recognize human IL‐23R‐IgG in surface plasmon resonance experiments, estimating the binding affinity in the sub‐ to nanomolar range. We further demonstrated that several REX variants bind to human leukemic cell lines K‐562, THP‐1 and Jurkat, and this binding correlated with IL‐23R cell‐surface expression. The REX125, REX009 and REX128 variants competed with the p19 protein for binding to THP‐1 cells. Moreover, the presence of REX125, REX009 and REX115 variants significantly inhibited the IL‐23‐driven expansion of IL‐17‐producing primary human CD4+ T‐cells. Thus, we conclude that unique IL‐23R antagonists derived from the ABD scaffold were generated that might be useful in designing novel anti‐inflammatory biologicals. Proteins 2014; 82:975–989. © 2013 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc. 相似文献
80.
Phenylethanoid glycosides are naturally occurring water-soluble compounds with remarkable biological properties that are widely distributed in the plant kingdom. Verbascoside is a phenylethanoid glycoside that was first isolated from mullein but is also found in several other plant species. It has also been produced by in vitro plant culture systems, including genetically transformed roots (so-called ‘hairy roots’). Verbascoside is hydrophilic in nature and possesses pharmacologically beneficial activities for human health, including antioxidant, anti-inflammatory and antineoplastic properties in addition to numerous wound-healing and neuroprotective properties. Recent advances with regard to the distribution, (bio)synthesis and bioproduction of verbascoside are summarised in this review. We also discuss its prominent pharmacological properties and outline future perspectives for its potential application. 相似文献