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1.
Ana V. Banko Ivana B. Lazarevic Miljan M. Folic Vojko B. Djukic Andja M. Cirkovic Danijela Z. Karalic Maja D. Cupic Tanja P. Jovanovic 《PloS one》2016,11(4)
Epstein-Barr virus (EBV) infection is a significant factor in the pathogenesis of nasopharyngeal carcinoma, especially in the undifferentiated carcinoma of nasopharyngeal type (UCNT, World Health Organization type III), which is the dominant histopathological type in high-risk areas. The major EBV oncogene is latent membrane protein 1 (LMP1). LMP1 gene shows variability with different tumorigenic and immunogenic potentials. EBV nuclear antigen 1 (EBNA1) regulates progression of EBV-related tumors; however, the influence of EBNA1 sequence variability on tumor pathogenesis is controversial. The aims of this study were to characterize polymorphisms of EBV genes in non-endemic nasopharyngeal carcinoma biopsies and to investigate potential sequence patterns that correlate with the clinical presentation of nasopharyngeal carcinoma. In total, 116 tumor biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), collected from 2008 to 2014, were evaluated in this study. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. The presence of EBV DNA was significantly distributed between TNM stages. LMP1 variability showed six variants, with the detection of the first China1 and North Carolina variants in European nasopharyngeal carcinoma biopsies. Newly discovered variants Srb1 and Srb2 were UCNT-specific LMP1 polymorphisms. The B95-8 and North Carolina variants are possible predictors for favorable TNM stages. In contrast, deletions in LMP1 are possible risk factors for the most disfavorable TNM stage, independent of EBNA2 or EBNA1 variability. A newly discovered EBNA1 subvariant, P-thr-sv-5, could be a potential diagnostic marker, as it represented a UCNT-specific EBNA1 subvariant. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, type 1/Med/P-thr was identified as a possible risk factor for TNM stage IVB or progression to the N3 stage. 相似文献
2.
Dementiev A Simonovic M Volz K Gettins PG 《The Journal of biological chemistry》2003,278(39):37881-37887
The serpin antithrombin is a slow thrombin inhibitor that requires heparin to enhance its reaction rate. In contrast, alpha1-proteinase inhibitor (alpha1PI) Pittsburgh (P1 Met --> Arg natural variant) inhibits thrombin 17 times faster than pentasaccharide heparin-activated antithrombin. We present here x-ray structures of free and S195A trypsin-bound alpha1PI Pittsburgh, which show that the reactive center loop (RCL) possesses a canonical conformation in the free serpin that does not change upon binding to S195A trypsin and that contacts the proteinase only between P2 and P2'. By inference from the structure of heparin cofactor II bound to S195A thrombin, this RCL conformation is also appropriate for binding to thrombin. Reaction rates of trypsin and thrombin with alpha1PI Pittsburgh and antithrombin and their P2 variants show that the low antithrombin-thrombin reaction rate results from the antithrombin RCL sequence at P2 and implies that, in solution, the antithrombin RCL must be in a similar canonical conformation to that found here for alpha1PI Pittsburgh, even in the nonheparin-activated state. This suggests a general, limited, canonical-like interaction between serpins and proteinases in their Michaelis complexes. 相似文献
3.
Isomerization of aspartate to isoaspartate occurs spontaneously in proteins, causes changes in protein structures, and correlates positively with the aging processes of many organisms, including Alzheimer disease in humans. Aspartate isomerization proceeds through an unstable cyclic succinimide intermediate. There are few protein structure determinations that have characterized the intermediates and products of this isomerization reaction. Here we report the discovery of an unusually stabilized succinimide ring in the 1.1A structure of the Escherichia coli CheY protein, as determined from a crystal eight years old. The ring is formed by the side-chain of aspartate 75 and the backbone nitrogen of glycine 76 in an exposed loop of the molecule. Stabilization of the succinimide is through interaction of a sulfate ion oxygen atom with the imide nitrogen atom. Formation of the ring caused conformational changes in the loop, but did not alter the overall structure of the protein. 相似文献
4.
Blue mould decay of stored onion bulbs caused by Penicillium polonicum,P. glabrum and P. expansum
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Nataša Duduk Marina Lazarević Aleksandra Žebeljan Miljan Vasić Ivana Vico 《Journal of Phytopathology》2017,165(10):662-669
Onion bulbs (Allium cepa L.) can be stored for up to 12 months to ensure their availability all year, but one of the limiting factors is decay caused by blue mould fungi. Postharvest development of blue mould is not only economically important, but also poses a health hazard due to mycotoxin contamination. Onion bulbs of different yellow and red cultivars with blue mould symptoms were collected from three storage facilities in Serbia. Pathogenic isolates were identified and characterized based on their molecular (partial β‐tubulin gene), morphological (micro‐ and macromorphology, and colony growth) and biochemical properties (analyses of indole metabolites via Ehrlich test). Three Penicillium species were identified: P. polonicum, P. glabrum and P. expansum. Virulence on inoculated onion bulbs varied significantly within isolates of P. glabrum, but the most virulent isolate of P. polonicum and P. glabrum did not differ, nor did they differ from an isolate of P. expansum. Variability in virulence of individual P. glabrum isolates corresponded to differences in their molecular and macromorphological characters. P. glabrum and P. expansum were identified for the first time as causal agents of onion bulb decay in Serbia. Data from this investigation provide insight into diversity of economically important and possibly toxigenic blue mould fungi which brings attention to their presence in storage facilities and therefore the necessity of the application of prevention measures. 相似文献
5.
The last step in ribosome-catalyzed protein synthesis is the hydrolytic release of the newly formed polypeptide from the P-site bound tRNA. Hydrolysis of the ester link of the peptidyl-tRNA is stimulated normally by the binding of release factors (RFs). However, an unacylated tRNA or just CCA binding to the ribosomal A site can also stimulate deacylation under some nonphysiological conditions. Although the sequence of events is well described by biochemical studies, the structural basis of the mechanism underlying this process is not well understood. Two new structures of the large ribosomal subunit of Haloarcula marismortui complexed with a peptidyl-tRNA analog in the P site and two oligonucleotide mimics of unacylated tRNA, CCA and CA, in the A site show that the binding of either CA or CCA induces a very similar conformational change in the peptidyl-transferase center as induced by aminoacyl-CCA. However, only CCA positions a water molecule appropriately to attack the carbonyl carbon of the peptidyl-tRNA and stabilizes the proper orientation of the ester link for hydrolysis. We, thus, conclude that both the ability of the O3′-hydroxyl group of the A-site A76 to position the water and the A-site CCA induced conformational change of the PTC are critical for the catalysis of the deacylation of the peptidyl-tRNA by CCA, and perhaps, an analogous mechanism is used by RFs. 相似文献
6.
J Ling KM Peterson I Simonovic D Söll M Simonovic 《The Journal of biological chemistry》2012,287(34):28518-28525
Accurate translation of mRNA into protein is a fundamental biological process critical for maintaining normal cellular functions. To ensure translational fidelity, aminoacyl-tRNA synthetases (aaRSs) employ pre-transfer and post-transfer editing activities to hydrolyze misactivated and mischarged amino acids, respectively. Whereas post-transfer editing, which requires either a specialized domain in aaRS or a trans-protein factor, is well described, the mechanism of pre-transfer editing is less understood. Here, we show that yeast mitochondrial threonyl-tRNA synthetase (MST1), which lacks an editing domain, utilizes pre-transfer editing to discriminate against serine. MST1 misactivates serine and edits seryl adenylate (Ser-AMP) in a tRNA-independent manner. MST1 hydrolyzes 80% of misactivated Ser-AMP at a rate 4-fold higher than that for the cognate threonyl adenylate (Thr-AMP) while releasing 20% of Ser-AMP into the solution. To understand the mechanism of pre-transfer editing, we solved the crystal structure of MST1 complexed with an analog of Ser-AMP. The binding of the Ser-AMP analog to MST1 induces conformational changes in the aminoacylation active site, and it positions a potential hydrolytic water molecule more favorably for nucleophilic attack. In addition, inhibition results reveal that the Ser-AMP analog binds the active site 100-fold less tightly than the Thr-AMP analog. In conclusion, we propose that the plasticity of the aminoacylation site in MST1 allows binding of Ser-AMP and the appropriate positioning of the hydrolytic water molecule. 相似文献
7.
Noel N Kim Miljan Stankovic Tulay T Cushman Irwin Goldstein Ricardo Munarriz Abdulmaged M Traish 《BMC physiology》2006,6(1):4-9
Background
Diabetes is associated with declining sexual function in women. However, the effects of diabetes on genital tissue structure, innervation and function remains poorly characterized. In control and streptozotocin-treated female rats, we investigated the effects of diabetes on vaginal blood flow, tissue morphology, and expression of arginase I, endothelial nitric oxide synthase (eNOS) and cGMP-dependent protein kinase (PKG), key enzymes that regulate smooth muscle relaxation. We further related these changes with estrogen receptor alpha (ERα) and androgen receptor (AR) expression. 相似文献8.
9.
Pigment epithelium-derived factor (PEDF), a serpin with potent anti-angiogenic and neurite outgrowth-promoting properties 总被引:1,自引:0,他引:1
Pigment epithelium-derived factor is a member of the serpin superfamily of proteins, but one that lacks inhibitory properties against either serine or cysteine proteinases. Nevertheless it possesses a number of physiological properties that make it a potentially important protein in regulation of angiogenesis, in neuronal cell survival and in protection of neurons from neurotoxic agents. It is also a protein that is highly up-regulated in the G0 phase of early-passage cells compared with rapidly proliferating cells or senescent cells, and so is also linked to both the cell cycle and cell senescence. The determination of a high resolution X-ray crystal structure of native PEDF provides insight into regions of the protein that may be involved in one or more of these functions. 相似文献
10.
Miljan Simonović Anupama K. Puppala 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(11):2463-2472