ArticleScientific reports2017
Interplay of buried histidine protonation and protein stability in prion misfolding.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 26 citations in OpenAlex.
- A role for pH dynamics regulating transcription factor DNA-binding selectivity.Nucleic acids research · 2025Article
- A pH-Dependent Coarse-Grained Model for Disordered Proteins: Histidine Interactions Modulate Conformational Ensembles.The journal of physical chemistry letters · 2024Article
- Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities.Journal of medicinal chemistry · 2024Article
- The Physical Basis for pH Sensitivity in Biomolecular Structure and Function, With Application to the Spike Protein of SARS-CoV-2.Frontiers in molecular biosciences · 2022Review
- Deuterium-Enhanced Raman Spectroscopy for Histidine pKBiophysical journal · 2020Article
- A seven-residue deletion in PrP leads to generation of a spontaneous prion formed from C-terminal C1 fragment of PrP.The Journal of biological chemistry · 2020Article
- Structural insight into conformational change in prion protein by breakage of electrostatic network around H187 due to its protonation.Scientific reports · 2019Article
- Article
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Authors and funding
11 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Misofolding of mammalian prion proteins (PrP) is believed to be the cause of a group of rare and fatal neurodegenerative diseases. Despite intense scrutiny however, the mechanism of the misfolding reaction remains unclear. We perform nuclear Magnetic Resonance and thermodynamic stability measurements on the C-terminal domains (residues 90-231) of two PrP variants exhibiting different pH-induced susceptibilities to aggregation: the susceptible hamster prion (GHaPrP) and its less susceptible rabbit homolog (RaPrP). The pKa of histidines in these domains are determined from titration experiments, and proton-exchange rates are measured at pH 5 and pH 7. A single buried highly conserved histidine, H187/H186 in GHaPrP/RaPrP, exhibited a markedly down shifted pKa ~5 for both proteins. However, noticeably larger pH-induced shifts in exchange rates occur for GHaPrP versus RaPrP. Analysis of the data indicates that protonation of the buried histidine destabilizes both PrP variants, but produces a more drastic effect in the less stable GHaPrP. This interpretation is supported by urea denaturation experiments performed on both PrP variants at neutral and low pH, and correlates with the difference in disease susceptibility of the two species, as expected from the documented linkage between destabilization of the folded state and formation of misfolded and aggregated species.
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