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Anuja Krishnan Santosh K. Verma Prashant Mani Rahul Gupta Suman Kundu Debi P. Sarkar 《Journal of virology》2009,83(4):1727-1741
Most paramyxovirus fusion proteins require coexpression of and activation by a homotypic attachment protein, hemagglutinin-neuraminidase (HN), to promote membrane fusion. However, the molecular mechanism of the activation remains unknown. We previously showed that the incorporation of a monohistidylated lipid into F-virosome (Sendai viral envelope containing only fusion protein) enhanced its fusion to hepatocytes, suggesting that the histidine residue in the lipid accelerated membrane fusion. Therefore, we explored whether a histidine moiety in HN could similarly direct activation of the fusion protein. In membrane fusion assays, the histidine substitution mutants of HN (H247A of Sendai virus and H245A of human parainfluenza virus 3) had impaired membrane fusion promotion activity without significant changes in other biological activities. Synthetic 30-mer peptides corresponding to regions of the two HN proteins containing these histidine residues rescued the fusion promoting activity of the mutants, whereas peptides with histidine residues substituted by alanine did not. These histidine-containing peptides also activated F-virosome fusion with hepatocytes both in the presence and in the absence of mutant HN in the virosome. We provide evidence that the HN-mimicking peptides promote membrane fusion, revealing a specific histidine “switch” in HN that triggers fusion. 相似文献
146.
Mani T Hennigan RF Foster LA Conrady DG Herr AB Ip W 《Molecular and cellular biology》2011,31(10):1983-1996
The neurofibromatosis type 2 tumor suppressor protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of plasma membrane-actin cytoskeleton linkers. For ezrin, phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding to the amino-terminal FERM domain is required for its conformational activation, proper subcellular localization, and function, but less is known about the role of phosphoinositide binding for merlin. Current evidence indicates that association with the membrane is important for merlin to function as a growth regulator; however, the mechanisms by which merlin localizes to the membrane are less clear. Here, we report that merlin binds phosphoinositides, including PIP(2), via a conserved binding motif in its FERM domain. Abolition of FERM domain-mediated phosphoinositide binding of merlin displaces merlin from the membrane and releases it into the cytosol without altering the folding of merlin. Importantly, a merlin protein whose FERM domain cannot bind phosphoinositide is defective in growth suppression. Retargeting the mutant merlin into the membrane using a dual-acylated amino-terminal decapeptide from Fyn is sufficient to restore the growth-suppressive properties to the mutant merlin. Thus, FERM domain-mediated phosphoinositide binding and membrane association are critical for the growth-regulatory function of merlin. 相似文献
147.
Hammel M Rey M Yu Y Mani RS Classen S Liu M Pique ME Fang S Mahaney BL Weinfeld M Schriemer DC Lees-Miller SP Tainer JA 《The Journal of biological chemistry》2011,286(37):32638-32650
The XRCC4-like factor (XLF)-XRCC4 complex is essential for nonhomologous end joining, the major repair pathway for DNA double strand breaks in human cells. Yet, how XLF binds XRCC4 and impacts nonhomologous end joining functions has been enigmatic. Here, we report the XLF-XRCC4 complex crystal structure in combination with biophysical and mutational analyses to define the XLF-XRCC4 interactions. Crystal and solution structures plus mutations characterize alternating XRCC4 and XLF head domain interfaces forming parallel super-helical filaments. XLF Leu-115 ("Leu-lock") inserts into a hydrophobic pocket formed by XRCC4 Met-59, Met-61, Lys-65, Lys-99, Phe-106, and Leu-108 in synergy with pseudo-symmetric β-zipper hydrogen bonds to drive specificity. XLF C terminus and DNA enhance parallel filament formation. Super-helical XLF-XRCC4 filaments form a positively charged channel to bind DNA and align ends for efficient ligation. Collective results reveal how human XLF and XRCC4 interact to bind DNA, suggest consequences of patient mutations, and support a unified molecular mechanism for XLF-XRCC4 stimulation of DNA ligation. 相似文献
148.
Aakanksha Wany Ashutosh Kumar Sivaramaiah Nallapeta Shivesh Jha Vinod K. Nigam Dev Mani Pandey 《Plant Growth Regulation》2014,73(2):133-145
Citronella oil is the main product of Java citronella grass (Cymbopogon winterianus Jowitt) rich in geraniol and citronellol, widely used in mosquito repellents and perfumeries. The age of the plant plays a key role in oil composition and its yield such that young leaves have lesser oil content than the mature leaves. Also, a remarkable difference between fresh and dried leaves regarding oil yield is observed. The various methods of extracting essential oils from citronella grass with respect to yield (%) were studied. Average percent yield in the manual extraction and hydro-distillation procedure was 0.8 and 1 % respectively, which was better as compared to steam distilled oil (0.7 %). The chromatographic analysis of essential oils with respect to standards geraniol and citronellol were studied by high performance thin layer chromatography (HPTLC) with n-hexane and ethyl acetate (3:2) as mobile phase followed by its separation on plates. The developed plates showed geraniol, citronellol and citronellal as major bands. The analysis of all extracted oil samples by means of electrospray ionization-mass spectrometry (ESI-MS) in the positive ion mode showed rapid mass fingerprints of constituents present in the samples according to the observed mass of standards. Furthermore, the analysis of vibrational spectra was accomplished with Fourier transform infra-red spectroscopy (FTIR) specifying all the functional groups as major peaks confirming all of them as monoterpene alcohols with conjugated double bonds. Thus, HPTLC, ESI-MS and FTIR studies evidenced that the two essential oil components were majorly present in the methanol extract suggesting methanol as a good extractant in the manual extraction process. 相似文献
149.
Mani P Grover Sara Ballouz Kaavya A Mohanasundaram Richard A George Craig D H Sherman Tamsyn M Crowley Merridee A Wouters 《BMC medical genomics》2014,7(Z1):S8
Background
Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials.Methods
We previously used Gentrepid (http://www.gentrepid.org) as a platform to predict 1,497 candidate genes for the seven complex diseases considered in the Wellcome Trust Case-Control Consortium genome-wide association study; namely Type 2 Diabetes, Bipolar Disorder, Crohn's Disease, Hypertension, Type 1 Diabetes, Coronary Artery Disease and Rheumatoid Arthritis. Here, we adopted a simple approach to integrate drug data from three publicly available drug databases: the Therapeutic Target Database, the Pharmacogenomics Knowledgebase and DrugBank; with candidate gene predictions from Gentrepid at the systems level.Results
Using the publicly available drug databases as sources of drug-target association data, we identified a total of 428 candidate genes as novel therapeutic targets for the seven phenotypes of interest, and 2,130 drugs feasible for repositioning against the predicted novel targets.Conclusions
By integrating genetic, bioinformatic and drug data, we have demonstrated that currently available drugs may be repositioned as novel therapeutics for the seven diseases studied here, quickly taking advantage of prior work in pharmaceutics to translate ground-breaking results in genetics to clinical treatments.150.
Manouchehrinejad Maryam Sahoo Kamalakanta Kaliyan Nalladurai Singh Hari Mani Sudhagar 《The International Journal of Life Cycle Assessment》2020,25(1):89-104
The International Journal of Life Cycle Assessment - Napier grass, one of the high yield perennial energy crops can be grown on marginal lands with minimal inputs, but with increased soil carbon... 相似文献