A combined simulation and experimental study was performed to investigate how methanol affects the structure of a model peptide BBA5. BBA5 forms a stable β-hairpin-α-helix structure in aqueous solutions. Molecular dynamics simulations were performed in water and methanol/water solutions using all-atom explicit models. NMR experiments were used to test the calculated results. The combined theoretical and experimental studies suggest that methanol strengthens the interactions between the polar backbone of the peptide and thus enhances the secondary structure formation; at the same time methanol weakens the hydrophobic interactions and results in an expansion of the hydrophobic core and an increase in gyration.
BackgroundThe Rocky Mountain elk (Cervus elaphus nelsoni) prion protein gene (PRNP) is polymorphic at codon 132, with leucine (L132) and methionine (M132) allelic variants present in the population. In elk experimentally inoculated with the chronic wasting disease (CWD) agent, different incubation periods are associated with PRNP genotype: LL132 elk survive the longest, LM132 elk are intermediate, and MM132 elk the shortest. The purpose of this study was to investigate potential mechanisms underlying variations in incubation period in elk of different prion protein genotypes. Elk calves of three PRNP genotypes (n = 2 MM132, n = 2 LM132, n = 4 LL132) were orally inoculated with brain homogenate from elk clinically affected with CWD.ResultsElk with longer incubation periods accumulated relatively less PrPSc in the brain than elk with shorter incubation periods. PrPSc accumulation in LM132 and MM132 elk was primarily neuropil-associated while glial-associated immunoreactivity was prominent in LL132 elk. The fibril stability of PrPSc from MM132 and LM132 elk were similar to each other and less stable than that from LL132 elk. Real-time quaking induced conversion assays (RT-QuIC) revealed differences in the ability of PrPSc seed from elk of different genotypes to convert recombinant 132 M or 132 L substrate.ConclusionsThis study provides further evidence of the importance of PRNP genotype in the pathogenesis of CWD of elk. The longer incubation periods observed in LL132 elk are associated with PrPSc that is more stable and relatively less abundant at the time of clinical disease. The biochemical properties of PrPSc from MM132 and LM132 elk are similar to each other and different to PrPSc from LL132 elk. The shorter incubation periods in MM132 compared to LM132 elk may be the result of genotype-dependent differences in the efficiency of propagation of PrPSc moieties present in the inoculum. A better understanding of the mechanisms by which the polymorphisms at codon 132 in elk PRNP influence disease pathogenesis will help to improve control of CWD in captive and free-ranging elk populations.
Background: CMP-pseudaminic acid formation and role in Bacillus thuringiensis flagellin glycosylation are unknown. Results: Seven enzymes are required to convert UDP-N-acetylglucosamine to CMP-pseudaminic acid; UDP-N-acetylglucosamine is converted to UDP-6-deoxy-D-N-acetylglucosamine-5,6-ene and then to UDP-4-keto-6-deoxy-L-N-acetylaltrosamine. Conclusion: Two previously undescribed enzymes initiate the CMP-pseudaminic acid pathway. Significance: Identifying a unique CMP-pseudaminic acid pathway in a Gram-positive bacterium may provide new opportunities to control bacterial flagellin glycosylation and pathogenicity.
Chronic wasting disease (CWD) is a fatal, progressive disease that affects cervid species, includingRocky mountain elk (Cervus elaphus nelsoni). There are 2 allelic variants in the elk prion protein gene: L132 (leucine) and M132 (methionine). Following experimental oral challenge with the CWD agent incubation periods are longest in LL132 elk, intermediate in ML132 elk, and shortest in MM132 elk. In order to ascertain whether such cWD-infected elk carry distinct prion strains, groups of Tg12 mice that express M132 elk prion protein were inoculated intracranially with brain homogenate from individual CWD-infected elk of various genotypes (LL132, LM132, or MM132). Brain samples were examined for microscopic changes and assessment of the biochemical properties of disease-associated prion protein (prp Sc ). On first passage, mice challenged with LL132 elk inoculum had prolonged incubation periods and greater prp Sc fibril stability compared to mice challenged with MM132 or LM132 inoculum. On second passage, relative incubation periods, western blot profiles, and neuropathology were maintained. These results suggest that the CWD prion isolated from LL132 elk is a novel CWD strain and that M132 PrP c is able to propagate some biophysical properties of the L132 PrP Sc conformation.Chronic wasting disease (CWD) is a fatal, progressive, neurodegenerative disease that has been reported in a number of cervid species including Rocky Mountain elk (Cervus elaphus nelsoni) and white-tailed deer (Odocoileus virginianus). Chronic wasting disease belongs to a group of diseases known as the transmissible spongiform encephalopathies (TSEs), or prion diseases, that are a group of neurodegenerative diseases in which a key feature is the accumulation of disease-associated prion protein (PrP Sc ) in the the brain.The prion protein gene (PRNP) of Rocky Mountain elk encodes for either methionine (M) or leucine (L) at codon 132 1,2 . The amino acid expressed at codon 132 greatly affects incubation periods in elk after experimental oral inoculation with the chronic wasting disease agent: elk expressing prion protein homozygous for leucine at codon 132 (hereafter referred to as LL132 elk) incubate approximately 1.5 times longer than LM132 elk and 3 times longer than MM132 elk 3,4 . We recently demonstrated that these variations in incubation period may be influenced by genotype-associated differences in the relative amount of PrP Sc in the brain and biochemical properties of PrP Sc , including fibril stability and amyloid formation rate 5 . TSE strains may be differentiated by host range, incubation period, clinical presentation, patterns of immunoreactivity or microscopic lesions in the brain, or the physiochemical properties of the PrP Sc itself (reviewed in 6 ). Prions lack genomic DNA to propagate strain information, and the strain properties are believed to be enciphered by the structure of the PrP Sc conformer 7-11 . Two different strains of CWD have been identified when CWD from white-tailed deer was passaged into Syrian hamsters 12 , ...
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