Mondal, B and Reddy, G (2020) A Transient Intermediate Populated in Prion Folding Leads to Domain Swapping. In: Biochemistry, 59 (1). pp. 114-124.
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Abstract
Aggregation of misfolded prion proteins causes fatal neurodegenerative disorders in both humans and animals. There is an extensive effort to identify the elusive aggregation-prone conformations (N*) of prions, which are early stage precursors to aggregation. We studied temperature- A nd force-induced unfolding of the structured C-terminal domain of mouse (moPrP) and human prion proteins (hPrP) using molecular dynamics simulations and coarse-grained protein models. We find that these proteins sparsely populate intermediate states bearing the features of N∗ and readily undergo domain-swapped dimerization by swapping the short β-strands present at the beginning of the C-terminal domain. The structure of the N∗ state is similar for both moPrP and hPrP, indicating a common pathogenic precursor across different species. Interestingly, disease-resistant hPrP (G127V) showed a drastic reduction in the population of the N∗ state further hinting a pathogenic connection to these partially denatured conformations. This study proposes a plausible runaway domain-swapping mechanism to describe the onset of prion aggregation.
| Item Type: | Journal Article |
|---|---|
| Publication: | Biochemistry |
| Publisher: | American Chemical Society |
| Additional Information: | The copyright for this article belongs to the Author. |
| Keywords: | Molecular dynamics; Neurodegenerative diseases, C-terminal domains; Domain-swapping mechanism; Human prion protein; Intermediate state; Molecular dynamics simulations; Neurodegenerative disorders; Temperature and force; Transient intermediate, Proteins, prion protein; prion protein, Article; carboxy terminal sequence; dimerization; human; molecular dynamics; nonhuman; oligomerization; pathogenicity; priority journal; propensity score; protein aggregation; protein conformation; protein domain; protein folding; protein structure; protein unfolding; animal; chemistry; metabolism; mouse; protein domain; protein multimerization; protein tertiary structure, Animals; Humans; Mice; Molecular Dynamics Simulation; Prion Proteins; Protein Domains; Protein Multimerization; Protein Structure, Tertiary; Protein Unfolding |
| Department/Centre: | Division of Chemical Sciences > Solid State & Structural Chemistry Unit |
| Date Deposited: | 04 Jan 2023 10:13 |
| Last Modified: | 04 Jan 2023 10:13 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79474 |
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