ArticleThe Journal of biological chemistry2015
Charge neutralization of the central lysine cluster in prion protein (PrP) promotes PrP(Sc)-like folding of recombinant PrP amyloids.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 46 citations in OpenAlex.
- D178N prion protein mutation endows RML prions with new strain properties that do not mimic human genetic prion diseases.Acta neuropathologica · 2026Article
- RNA as a component of scrapie fibrils.Scientific reports · 2024Article
- Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.Acta neuropathologica · 2024Article
- Seed amplification and RT-QuIC assays to investigate protein seed structures and strains.Cell and tissue research · 2023Review
- Cryo-EM of prion strains from the same genotype of host identifies conformational determinants.PLoS pathogens · 2022Article
- Defining the Protein Seeds of Neurodegeneration using Real-Time Quaking-Induced Conversion Assays.Biomolecules · 2020Review
- Isolation of infectious, non-fibrillar and oligomeric prions from a genetic prion disease.Brain : a journal of neurology · 2020Article
- Challenges and Advances in Antemortem Diagnosis of Human Transmissible Spongiform Encephalopathies.Frontiers in bioengineering and biotechnology · 2020Review
- Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications.International journal of molecular sciences · 2019Review
- Mammalian amyloidogenic proteins promote prion nucleation in yeast.The Journal of biological chemistry · 2018Article
- A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location.Antimicrobial agents and chemotherapy · 2018Article
- Characterization of mutations inNeuropsychiatric disease and treatment · 2018Review
- PrP P102L and Nearby Lysine Mutations Promote SpontaneousJournal of virology · 2017Article
- Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates.PLoS pathogens · 2017Article
- Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity.PLoS pathogens · 2017Article
- Unraveling Prion Protein Interactions with Aptamers and Other PrP-Binding Nucleic Acids.International journal of molecular sciences · 2017Review
- Isolation of a Defective Prion Mutant from Natural Scrapie.PLoS pathogens · 2016Article
- The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases.Nature protocols · 2016Article
- Molecular tweezers for lysine and arginine - powerful inhibitors of pathologic protein aggregation.Chemical communications (Cambridge, England) · 2016Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The structure of the infectious form of prion protein, PrP(Sc), remains unclear. Most pure recombinant prion protein (PrP) amyloids generated in vitro are not infectious and lack the extent of the protease-resistant core and solvent exclusion of infectious PrP(Sc), especially within residues ∼90-160. Polyanionic cofactors can enhance infectivity and PrP(Sc)-like characteristics of such fibrils, but the mechanism of this enhancement is unknown. In considering structural models of PrP(Sc) multimers, we identified an obstacle to tight packing that might be overcome with polyanionic cofactors, namely, electrostatic repulsion between four closely spaced cationic lysines within a central lysine cluster of residues 101-110. For example, in our parallel in-register intermolecular β-sheet model of PrP(Sc), not only would these lysines be clustered within the 101-110 region of the primary sequence, but they would have intermolecular spacings of only ∼4.8 Å between stacked β-strands. We have now performed molecular dynamics simulations predicting that neutralization of the charges on these lysine residues would allow more stable parallel in-register packing in this region. We also show empirically that substitution of these clustered lysine residues with alanines or asparagines results in recombinant PrP amyloid fibrils with extended proteinase-K resistant β-sheet cores and infrared spectra that are more reminiscent of bona fide PrP(Sc). These findings indicate that charge neutralization at the central lysine cluster is critical for the folding and tight packing of N-proximal residues within PrP amyloid fibrils. This charge neutralization may be a key aspect of the mechanism by which anionic cofactors promote PrP(Sc) formation.
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