ArticleThe Journal of biological chemistry2014
Acid-induced molten globule state of a prion protein: crucial role of Strand 1-Helix 1-Strand 2 segment.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 49 citations in OpenAlex.
- Prion propagation is controlled by discrete structural regions of PrP rather than overall stability.The Journal of biological chemistry · 2026Article
- PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features.Journal of neurology · 2025Article
- Review
- Destabilization of polar interactions in the prion protein triggers misfolding and oligomerization.Protein science : a publication of the Protein Society · 2021Article
- Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic.International journal of molecular sciences · 2021Article
- Mechanism of misfolding of the human prion protein revealed by a pathological mutation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- A look back at the molten globule state of proteins: thermodynamic aspects.Biophysical reviews · 2019Review
- Formation and properties of amyloid fibrils of prion protein.Biophysical reviews · 2018Review
- Article
- Prion protein dynamics before aggregation.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions.PloS one · 2017Article
- Partially Unfolded Forms of the Prion Protein Populated under Misfolding-promoting Conditions: CHARACTERIZATION BY HYDROGEN EXCHANGE MASS SPECTROMETRY AND NMR.The Journal of biological chemistry · 2015Article
- A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein.Structure (London, England : 1993) · 2015Article
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3 authors at 1 institution in 1 country.
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Abstract
The conversion of a cellular prion protein (PrP(C)) to its pathogenic isoform (PrP(Sc)) is a critical event in the pathogenesis of prion diseases. Pathogenic conversion is usually associated with the oligomerization process; therefore, the conformational characteristics of the pre-oligomer state may provide insights into the conversion process. Previous studies indicate that PrP(C) is prone to oligomer formation at low pH, but the conformation of the pre-oligomer state remains unknown. In this study, we systematically analyzed the acid-induced conformational changes of PrP(C) and discovered a unique acid-induced molten globule state at pH 2.0 termed the "A-state." We characterized the structure of the A-state using far/near-UV CD, 1-anilino-8-naphthalene sulfonate fluorescence, size exclusion chromatography, and NMR. Deuterium exchange experiments with NMR detection revealed its first unique structure ever reported thus far; i.e. the Strand 1-Helix 1-Strand 2 segment at the N terminus was preferentially unfolded, whereas the Helix 2-Helix 3 segment at the C terminus remained marginally stable. This conformational change could be triggered by the protonation of Asp(144), Asp(147), and Glu(196), followed by disruption of key salt bridges in PrP(C). Moreover, the initial population of the A-state at low pH (pH 2.0-5.0) was well correlated with the rate of the β-rich oligomer formation, suggesting that the A-state is the pre-oligomer state. Thus, the specific conformation of the A-state would provide crucial insights into the mechanisms of oligomerization and further pathogenic conversion as well as facilitating the design of novel medical chaperones for treating prion diseases.
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