Dataset Information

How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides.

ABSTRACT: The amino acid sequences in the amyloidogenic region (amino acids 108-144) of several mammalian prion proteins were compared and variations were found to occur at residues 109 (M or L), 112 (M or V), 129 (M, V, or L), 135 (N or S), 138 (M, L, or I), 139 (M or I), and 143 (N or S). Using the bovine PrP peptide (residues 108-144 based on the numbering of the human prion protein sequence) as a control peptide, several peptides with one amino acid differing from that of the bovine PrP peptide at residues 109, 112, 135, 138, 139, or 143 and several mammalian PrP peptides were synthesized, and the effects of these amino acid substitutions on the amyloidogenic properties of these peptides were compared and discussed on the basis of the chemical and structural properties of amino acids. Our results showed that the V112M substitution accelerated nucleation of amyloidogenesis, while the N143S and I139M substitutions retarded nucleation. These effects tended to cancel each other out when two substitutions with opposite effects were present on the same peptide. Moreover, acceleration or inhibition of nucleation was not necessarily correlated with effect on seeding efficiency. Using amyloid fibrils prepared from the bovine PrP peptide as seeds, the seeding efficiency for the monomer peptides with the M129L, S135N, N143S, or I139M substitution was decreased compared to that for bPrP peptide. Of all the mammalian peptides used in this study, the dog, mule deer, and pig PrP peptides had the lowest seeding efficiencies.

SUBMITTER: Chuang CC

PROVIDER: S-EPMC3776267 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides.

Chuang Chi-Chen CC Liao Tai-Yan TY Chen Eric H-L EH Chen Rita P-Y RP

Amino acids 20130605 4

The amino acid sequences in the amyloidogenic region (amino acids 108-144) of several mammalian prion proteins were compared and variations were found to occur at residues 109 (M or L), 112 (M or V), 129 (M, V, or L), 135 (N or S), 138 (M, L, or I), 139 (M or I), and 143 (N or S). Using the bovine PrP peptide (residues 108-144 based on the numbering of the human prion protein sequence) as a control peptide, several peptides with one amino acid differing from that of the bovine PrP peptide at res ...[more]

PMID: 23736988

Similar Datasets

Project description:Background & aimsSofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure.MethodsWe collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon.ResultsWe identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system.ConclusionsA common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.

Dataset Information

How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides.

Publications

How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets