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The role of RNA in mammalian prion protein conversion

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Abstract Prion diseases remain a challenge to modern science in the 21st century because of their capacity for transmission without an encoding nucleic acid. PrPSc, the infectious and alternatively folded form of the PrP prion protein, is capable of self‐replication, using PrPC, the properly folded form of PrP, as a template. This process is associated with neuronal death and the clinical manifestation of prion‐based diseases. Unfortunately, little is known about the mechanisms that drive this process. Over the last decade, the theory that a nucleic acid, such as an RNA molecule, might be involved in the process of prion structural conversion has become more widely accepted; such a nucleic acid would act as a catalyst rather than encoding genetic information. Significant amounts of data regarding the interactions of PrP with nucleic acids have created a new foundation for understanding prion conversion and the transmission of prion diseases. Our knowledge has been enhanced by the characterization of a large group of RNA molecules known as non‐coding RNAs, which execute a series of important cellular functions, from transcriptional regulation to the modulation of neuroplasticity. The RNA‐binding properties of PrP along with the competition with other polyanions, such as glycosaminoglycans and nucleic acid aptamers, open new avenues for therapy. WIREs RNA 2012, 3:415–428. doi: 10.1002/wrna.118 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease

Differences in the predicted DNA‐binding sites, electrostatic potential distribution, and secondary structure content among PrP molecules from distinct mammalian species. (a) Human, PDB: 1QM1; (b) cattle, PDB: 1DWZ; (c) mouse, PDB: 1XYX; (d) Syrian hamster, PDB: 1B10; and (e) rabbit, PDB: 2FJ3. Ribbon representations of the secondary and tertiary structures of the PrPs are shown in the left panel. All surface graphs were generated using MolMol.23 DNA‐binding predictions (center panel, colored blue) were performed using DISPLAR.24 Distributions of electrostatic potentials are shown in the right panel, colored blue for positive charge, and red for negative charge.

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Interaction between PrP, RNA, and glycosaminoglycans (GAGs). rPrP23‐231 has a globular C‐terminal domain (blue, α helices; red, β‐sheet), and a highly flexible N‐terminal domain (green) that assumes different spatial positions with LMWHep (pink) and other GAGs, favors self‐association, and leads to reversible protein aggregation. After disaggregation, rPrP23‐231 remains bond to LMWHep and presents a similar fold to the free monomer, with no scrapie‐like conformation, but with a less flexible Nterminus. RNA molecules (orange) bind to rPrP23‐231 at its N‐terminal domain leading to irreversible aggregation. Interestingly, RNA is not able to induce aggregation of LMWHep–PrP complex.

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Major non‐coding RNA (ncRNA) classes and functions. All ncRNAs represented execute regulatory functions. PAR, promoter‐associated RNA; lncRNA, long non‐coding RNA (>200 nt); short interfering RNA, small interference RNA (21–22 nt); miRNA, microRNA (∼22 nt); snoRNA, small nucleolar RNA; sdRNA, sno‐derived RNA.

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Proposed models for PrPC conversion into PrPSc. (a) PrPSc is the only molecule responsible for structural conversion of PrPC into new PrPSc. A third macromolecule is responsible for PrPC conversion into PrPSc with two possible courses of action. (b) The catalyst molecule is directly responsible for PrPC conversion into PrPSc. (c) The cofactor molecule acts as a catalyst, facilitating PrPC conversion into PrPSc. (d) The conformational transition is separated by a large energetic barrier that is associated with unfolding and oligomerization. (e) A cofactor molecule acts as a catalyst, lowering the energy barrier between PrPC and PrPSc, facilitating conversion.

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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA in Disease and Development > RNA in Disease

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