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Search Results: 1 - 10 of 130767 matches for " Ilia V. Baskakov "
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The Evolution of Transmissible Prions: The Role of Deformed Templating
Natallia Makarava,Ilia V. Baskakov
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003759
Assessment of Strain-Specific PrPSc Elongation Rates Revealed a Transformation of PrPSc Properties during Protein Misfolding Cyclic Amplification
Nuria Gonzalez-Montalban, Ilia V. Baskakov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041210
Abstract: Prion replication is believed to consist of two components, a growth or elongation of infectious isoform of the prion protein (PrPSc) particles and their fragmentation, a process that provides new replication centers. The current study introduced an experimental approach that employs Protein Misfolding Cyclic Amplification with beads (PMCAb) and relies on a series of kinetic experiments for assessing elongation rates of PrPSc particles. Four prion strains including two strains with short incubation times to disease (263K and Hyper) and two strains with very long incubation times (SSLOW and LOTSS) were tested. The elongation rate of brain-derived PrPSc was found to be strain-specific. Strains with short incubation times had higher rates than strains with long incubation times. Surprisingly, the strain-specific elongation rates increased substantially for all four strains after they were subjected to six rounds of serial PMCAb. In parallel to an increase in elongation rates, the percentages of diglycosylated PrP glycoforms increased in PMCAb-derived PrPSc comparing to those of brain-derived PrPSc. These results suggest that PMCAb selects the same molecular features regardless of strain initial characteristics and that convergent evolution of PrPSc properties occurred during in vitro amplification. These results are consistent with the hypothesis that each prion strain is comprised of a variety of conformers or ‘quasi-species’ and that change in the prion replication environment gives selective advantage to those conformers that replicate most effectively under specific environment.
Light-Dependent Electrogenic Activity of Cyanobacteria
John M. Pisciotta,Yongjin Zou,Ilia V. Baskakov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010821
Abstract: Cyanobacteria account for 20–30% of Earth's primary photosynthetic productivity and convert solar energy into biomass-stored chemical energy at the rate of ~450 TW [1]. These single-cell microorganisms are resilient predecessors of all higher oxygenic phototrophs and can be found in self-sustaining, nitrogen-fixing communities the world over, from Antarctic glaciers to the Sahara desert [2].
Cellular cochain algebras and torus actions
Ilia V. Baskakov,Victor M. Buchstaber,Taras E. Panov
Mathematics , 2004,
Abstract: We prove that the integral cohomology algebra of the moment-angle complex Z_K, or of the corresponding coordinate subspace arrangement complement U(K), is isomorphic to the Tor-algebra of the face ring Z[K] of simplicial complex K.
Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and Toxicity
Young Jin Lee,Regina Savtchenko,Valeriy G. Ostapchenko,Natallia Makarava,Ilia V. Baskakov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020244
Abstract: According to the prevailing view, soluble oligomers or small fibrillar fragments are considered to be the most toxic species in prion diseases. To test this hypothesis, two conformationally different amyloid states were produced from the same highly pure recombinant full-length prion protein (rPrP). The cytotoxic potential of intact fibrils and fibrillar fragments generated by sonication from these two states was tested using cultured cells.
Sialylation of Prion Protein Controls the Rate of Prion Amplification, the Cross-Species Barrier, the Ratio of PrPSc Glycoform and Prion Infectivity
Elizaveta Katorcha,Natallia Makarava,Regina Savtchenko,Alessandra d′Azzo,Ilia V. Baskakov
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004366
Abstract: The central event underlying prion diseases involves conformational change of the cellular form of the prion protein (PrPC) into the disease-associated, transmissible form (PrPSc). PrPC is a sialoglycoprotein that contains two conserved N-glycosylation sites. Among the key parameters that control prion replication identified over the years are amino acid sequence of host PrPC and the strain-specific structure of PrPSc. The current work highlights the previously unappreciated role of sialylation of PrPC glycans in prion pathogenesis, including its role in controlling prion replication rate, infectivity, cross-species barrier and PrPSc glycoform ratio. The current study demonstrates that undersialylated PrPC is selected during prion amplification in Protein Misfolding Cyclic Amplification (PMCAb) at the expense of oversialylated PrPC. As a result, PMCAb-derived PrPSc was less sialylated than brain-derived PrPSc. A decrease in PrPSc sialylation correlated with a drop in infectivity of PMCAb-derived material. Nevertheless, enzymatic de-sialylation of PrPC using sialidase was found to increase the rate of PrPSc amplification in PMCAb from 10- to 10,000-fold in a strain-dependent manner. Moreover, de-sialylation of PrPC reduced or eliminated a species barrier of for prion amplification in PMCAb. These results suggest that the negative charge of sialic acid controls the energy barrier of homologous and heterologous prion replication. Surprisingly, the sialylation status of PrPC was also found to control PrPSc glycoform ratio. A decrease in PrPC sialylation levels resulted in a higher percentage of the diglycosylated glycoform in PrPSc. 2D analysis of charge distribution revealed that the sialylation status of brain-derived PrPC differed from that of spleen-derived PrPC. Knocking out lysosomal sialidase Neu1 did not change the sialylation status of brain-derived PrPC, suggesting that Neu1 is not responsible for desialylation of PrPC. The current work highlights previously unappreciated role of PrPC sialylation in prion diseases and opens multiple new research directions, including development of new therapeutic approaches.
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease
Natallia Makarava,Gabor G. Kovacs,Regina Savtchenko,Irina Alexeeva,Herbert Budka,Robert G. Rohwer,Ilia V. Baskakov
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002419
Abstract: The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.
Highly Efficient Protein Misfolding Cyclic Amplification
Nuria Gonzalez-Montalban equal contributor,Natallia Makarava equal contributor,Valeriy G. Ostapchenko,Regina Savtchenk,Irina Alexeeva,Robert G. Rohwer,Ilia V. Baskakov
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1001277
Abstract: Protein misfolding cyclic amplification (PMCA) provides faithful replication of mammalian prions in vitro and has numerous applications in prion research. However, the low efficiency of conversion of PrPC into PrPSc in PMCA limits the applicability of PMCA for many uses including structural studies of infectious prions. It also implies that only a small sub-fraction of PrPC may be available for conversion. Here we show that the yield, rate, and robustness of prion conversion and the sensitivity of prion detection are significantly improved by a simple modification of the PMCA format. Conducting PMCA reactions in the presence of Teflon beads (PMCAb) increased the conversion of PrPC into PrPSc from ~10% to up to 100%. In PMCAb, a single 24-hour round consistently amplified PrPSc by 600-700-fold. Furthermore, the sensitivity of prion detection in one round (24 hours) increased by 2-3 orders of magnitude. Using serial PMCAb, a 1012-fold dilution of scrapie brain material could be amplified to the level detectible by Western blotting in 3 rounds (72 hours). The improvements in amplification efficiency were observed for the commonly used hamster 263K strain and for the synthetic strain SSLOW that otherwise amplifies poorly in PMCA. The increase in the amplification efficiency did not come at the expense of prion replication specificity. The current study demonstrates that poor conversion efficiencies observed previously have not been due to the scarcity of a sub-fraction of PrPC susceptible to conversion nor due to limited concentrations of essential cellular cofactors required for conversion. The new PMCAb format offers immediate practical benefits and opens new avenues for developing fast ultrasensitive assays and for producing abundant quantities of PrPSc in vitro.
Ubiquitination-Induced Fluorescence Complementation (UiFC) for Detection of K48 Ubiquitin Chains In Vitro and in Live Cells
Zhiliang Chen, Yongwang Zhong, Yang Wang, Shan Xu, Zheng Liu, Ilia V. Baskakov, Mervyn J. Monteiro, Mariusz Karbowski, Yuxian Shen, Shengyun Fang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073482
Abstract: Proteins can be modified with eight homogenous ubiquitin chains linked by an isopeptide bond between the C-terminus of one ubiquitin and an amine from one of the seven lysines or the N-terminal methionine of the next ubiquitin. These topologically distinct ubiquitin chains signal for many essential cellular functions, such as protein degradation, cell cycle progression, DNA repair, and signal transduction. The lysine 48 (K48)-linked ubiquitin chain is one of the most abundant chains and a major proteasome-targeting signal in cells. Despite recent advancements in imaging linkage-specific polyubiquitin chains, no tool is available for imaging K48 chains in live cells. Here we report on a ubiquitination-induced fluorescence complementation (UiFC) assay for detecting K48 ubiquitin chains in vitro and in live cells. For this assay, two nonfluorescent fragments of a fluorescent protein were fused to the ubiquitin-interacting motifs (UIMs) of epsin1 protein. Upon simultaneous binding to a ubiquitin chain, the nonfluorescent fragments of the two fusion proteins are brought in close proximity to reconstitute fluorescence. When used in vitro, UiFC preferentially detected K48 ubiquitin chains with excellent signal-to-noise ratio. Time-lapse imaging revealed that UiFC is capable of monitoring increases in polyubiquitination induced by treatment with proteasome inhibitor, by agents that induce stress, and during mitophagy in live cells.
Protease-Sensitive Synthetic Prions
David W. Colby,Rachel Wain,Ilia V. Baskakov,Giuseppe Legname,Christina G. Palmer,Hoang-Oanh B. Nguyen,Azucena Lemus,Fred E. Cohen,Stephen J. DeArmond,Stanley B. Prusiner
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000736
Abstract: Prions arise when the cellular prion protein (PrPC) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrPSc. Frequently, PrPSc is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrPSc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600–750 days in Tg4053 mice, which exhibited sPrPSc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrPSc.
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