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Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid ?-protein oligomerization.

ABSTRACT: Amyloid ?-protein (A ?) assembles into oligomers that play a seminal role in Alzheimer's disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of A ? oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant A ? alloforms in the brain, A ? 40 and A ? 42, whereas the [K28A] substitution exerts only a moderate effect. Here, folding and oligomerization of [A16]A ? 40, [A28]A ? 40, [A16]A ? 42, and [A28]A ? 42 are examined by discrete molecular dynamics (DMD) combined with a four-bead implicit solvent force field, DMD4B-HYDRA, and compared to A ? 40 and A ? 42 oligomer formation. Our results show that both substitutions promote A ? 40 and A ? 42 oligomerization and that structural changes to oligomers are substitution- and alloform-specific. The [K28A] substitution increases solvent-accessible surface area of hydrophobic residues and the intrapeptide N-to-C terminal distance within oligomers more than the [K16A] substitution. The [K16A] substitution decreases the overall ?-strand content, whereas the [K28A] substitution exerts only a modest change. Substitution-specific tertiary and quaternary structure changes indicate that the [K16A] substitution induces formation of more compact oligomers than the [K28A] substitution. If the structure-function paradigm applies to A ? oligomers, then the observed substitution-specific structural changes in A ? 40 and A ? 42 oligomers are critical for understanding the structural basis of A ? oligomer toxicity and correct identification of therapeutic targets against AD.

SUBMITTER: Zganec M

PROVIDER: S-EPMC4942424 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization.

Žganec Matjaž M Kruczek Nicholas N Urbanc Brigita B

Journal of biological physics 20160507 3

Amyloid β-protein (A β) assembles into oligomers that play a seminal role in Alzheimer's disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of A β oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant A β alloforms in the brain, A β 40 and A β 42, whereas the [K28A] substitution exerts only a moderate effect. Here, fold ...[more]

PMID: 27155979

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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

Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid ?-protein oligomerization.

Publications

Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization.

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