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71.
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
72.
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
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74.
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
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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
77.
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
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79.
Bichen Zhang Kalina Lapenta Qi Wang Jin Hyun Nam Dongjun Chung Marie E. Robert Michael H. Nathanson Xiaoyong Yang 《The Journal of biological chemistry》2021,297(1)
Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT–TFF2 axis in the process of fibrogenesis. 相似文献
80.
Kalina I. Alipieva Ilkay Erdogan Orhan I. Irem Tatli Cankaya Emanuela P. Kostadinova Milen I. Georgiev 《Phytochemistry Reviews》2014,13(2):417-444
The genus Verbascum (mulleins), belonging to the family Scrophulariaceae, comprises about 360 species of flowering plants. The leaves, flowers and whole aerial parts of Verbascum spp. have been widely used in traditional medicine for the treatment of respiratory and inflammatory disorders and also display powerful wound healing activity. Verbascum species are found to accumulate several groups of bioactive molecules, therefore they might be utilized as attractive sources of new (drug) leads. The present review attempts to provide an up-to-date comprehensive overview on phytochemical and pharmacological aspects of Verbacum spp. research along with some successful examples of growing (and transforming) mulleins in vitro. 相似文献