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991.
992.
Ann L. Wozniak Stephen Griffin David Rowlands Mark Harris MinKyung Yi Stanley M. Lemon Steven A. Weinman 《PLoS pathogens》2010,6(9)
The hepatitis C virus (HCV) p7 protein is critical for virus production and an attractive antiviral target. p7 is an ion channel when reconstituted in artificial lipid bilayers, but channel function has not been demonstrated in vivo and it is unknown whether p7 channel activity plays a critical role in virus production. To evaluate the contribution of p7 to organelle pH regulation and virus production, we incorporated a fluorescent pH sensor within native, intracellular vesicles in the presence or absence of p7 expression. p7 increased proton (H+) conductance in vesicles and was able to rapidly equilibrate H+ gradients. This conductance was blocked by the viroporin inhibitors amantadine, rimantadine and hexamethylene amiloride. Fluorescence microscopy using pH indicators in live cells showed that both HCV infection and expression of p7 from replicon RNAs reduced the number of highly acidic (pH<5) vesicles and increased lysosomal pH from 4.5 to 6.0. These effects were not present in uninfected cells, sub-genomic replicon cells not expressing p7, or cells electroporated with viral RNA containing a channel-inactive p7 point mutation. The acidification inhibitor, bafilomycin A1, partially restored virus production to cells electroporated with viral RNA containing the channel inactive mutation, yet did not in cells containing p7-deleted RNA. Expression of influenza M2 protein also complemented the p7 mutant, confirming a requirement for H+ channel activity in virus production. Accordingly, exposure to acid pH rendered intracellular HCV particles non-infectious, whereas the infectivity of extracellular virions was acid stable and unaffected by incubation at low pH, further demonstrating a key requirement for p7-induced loss of acidification. We conclude that p7 functions as a H+ permeation pathway, acting to prevent acidification in otherwise acidic intracellular compartments. This loss of acidification is required for productive HCV infection, possibly through protecting nascent virus particles during an as yet uncharacterized maturation process. 相似文献
993.
Ebbing P. de Jong Hongwei Xie Getiria Onsongo Matthew D. Stone Xiao-Bing Chen Joel A. Kooren Eric W. Refsland Robert J. Griffin Frank G. Ondrey Baolin Wu Chap T. Le Nelson L. Rhodus John V. Carlis Timothy J. Griffin 《PloS one》2010,5(6)
Background
Oral cancer survival rates increase significantly when it is detected and treated early. Unfortunately, clinicians now lack tests which easily and reliably distinguish pre-malignant oral lesions from those already transitioned to malignancy. A test for proteins, ones found in non-invasively-collected whole saliva and whose abundances distinguish these lesion types, would meet this critical need.Methodology/Principal Findings
To discover such proteins, in a first-of-its-kind study we used advanced mass spectrometry-based quantitative proteomics analysis of the pooled soluble fraction of whole saliva from four subjects with pre-malignant lesions and four with malignant lesions. We prioritized candidate biomarkers via bioinformatics and validated selected proteins by western blotting. Bioinformatic analysis of differentially abundant proteins and initial western blotting revealed increased abundance of myosin and actin in patients with malignant lesions. We validated those results by additional western blotting of individual whole saliva samples from twelve other subjects with pre-malignant oral lesions and twelve with malignant oral lesions. Sensitivity/specificity values for distinguishing between different lesion types were 100%/75% (p = 0.002) for actin, and 67%/83% (p<0.00001) for myosin in soluble saliva. Exfoliated epithelial cells from subjects'' saliva also showed increased myosin and actin abundance in those with malignant lesions, linking our observations in soluble saliva to abundance differences between pre-malignant and malignant cells.Conclusions/Significance
Salivary actin and myosin abundances distinguish oral lesion types with sensitivity and specificity rivaling other non-invasive oral cancer tests. Our findings provide a promising starting point for the development of non-invasive and inexpensive salivary tests to reliably detect oral cancer early. 相似文献994.
Wang Z Collighan RJ Gross SR Danen EH Orend G Telci D Griffin M 《The Journal of biological chemistry》2010,285(51):40212-40229
Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, we show that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and β1 integrin co-signaling pathway. By using α5 null cells, β1 integrin functional blocking antibody, and a α5β1 integrin targeting peptide A5-1, we demonstrate that the α5 and β1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKCα is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains. 相似文献
995.
William D. Schmitz Allison B. Brenner Joanne J. Bronson Jonathan L. Ditta Corrine R. Griffin Yu-Wen Li Nicholas J. Lodge Thaddeus F. Molski Richard E. Olson Xiaoliang Zhuo John E. Macor 《Bioorganic & medicinal chemistry letters》2010,20(12):3579-3583
A series of 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previously observed in a related N3-phenylpyrazinone structure was minimized by incorporation of the additional ring nitrogen found in the triazinones. 相似文献
996.
Zhang J Chalmers MJ Stayrook KR Burris LL Garcia-Ordonez RD Pascal BD Burris TP Dodge JA Griffin PR 《Structure (London, England : 1993)》2010,18(10):1332-1341
Regulation of nuclear receptor (NR) activity is driven by alterations in the conformational dynamics of the receptor upon ligand binding. Previously, we demonstrated that hydrogen/deuterium exchange (HDX) can be applied to determine novel mechanism of action of PPARγ ligands and in predicting tissue specificity of selective estrogen receptor modulators. Here, we applied HDX to probe the conformational dynamics of the ligand binding domain (LBD) of the vitamin D receptor (VDR) upon binding its natural ligand 1α,25-dihydroxyvitamin D3 (1,25D3), and two analogs, alfacalcidol and ED-71. Comparison of HDX profiles from ligands in complex with the LBD with full-length receptor bound to its cognate receptor retinoid X receptor (RXR) revealed unique receptor dynamics that could not be inferred from static crystal structures. These results demonstrate that ligands modulate the dynamics of the heterodimer interface as well as provide insight into the role of AF-2 dynamics in the action of VDR partial agonists. 相似文献
997.
998.
999.
Parker J. Nichols Isaac Falconer Aaron Griffin Colin Mant Robert Hodges Christopher J. McKnight Beat Vgeli Liliya Vugmeyster 《Protein science : a publication of the Protein Society》2020,29(7):1641-1654
We have investigated the effect of deuteration of non‐exchangeable protons on protein global thermal stability, hydrophobicity, and local flexibility using well‐known thermostable model systems such as the villin headpiece subdomain (HP36) and the third immunoglobulin G‐binding domain of protein G (GB3). Reversed‐phase high‐performance liquid chromatography (RP‐HPLC) measurements as a function of temperature probe global thermal stability in the presence of acetonitrile, while differential scanning calorimetry determines thermal stability in solution. Both indicate small but measurable changes in the order of several degrees. RP‐HPLC also permitted quantification of the effect of deuteration of just three core phenylalanine side chains of HP36. NMR dynamics investigation has focused on methyl axes motions using cross‐correlated relaxation measurements. The analysis of order parameters provided a complex picture indicating that deuteration generally increases motional amplitudes of sub‐nanosecond motion in GB3 but decreases those in HP36. Combined with earlier dynamics measurements at Cα–Cβ sites and backbone sites of GB3, which probed slower time scales, the results point to the need to probe multiple atoms in the protein and variety of time scales to the discern the full complexity of the effects of deuteration on dynamics. 相似文献
1000.
Ross A. Breckenridge Izabela Piotrowska Keat-Eng Ng Timothy J. Ragan James A. West Surendra Kotecha Norma Towers Michael Bennett Petra C. Kienesberger Ryszard T. Smolenski Hillary K. Siddall John L. Offer Mihaela M. Mocanu Derek M. Yelon Jason R. B. Dyck Jules L. Griffin Andrey Y. Abramov Alex P. Gould Timothy J. Mohun 《PLoS biology》2013,11(9)