The “Jekyll and Hyde” Actions of Nucleic Acids on the Prion-like Aggregation of Proteins

Abstract

Protein misfolding results in devastating degenerative diseases and cancer. Among the culprits involved in these illnesses are prions and prion-like proteins, which can propagate by converting normal proteins to the wrong conformation. For spongiform encephalopathies, a real prion can be transmitted among individuals. In other disorders, the bona fide prion characteristics are still under investigation. Besides inducing misfolding of native proteins, prions bind nucleic acids and other polyanions. Here, we discuss how nucleic acid binding might influence protein misfolding for both disease-related and benign, functional prions and why the line between bad and good amyloids might be more subtle than previously thought.

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

“…49 Physiologically, many MLOs exist for limited time and their biogenesis is highly controlled. 7 In fact, Figure 6 shows that both N-(residues F I G U R E 8 Aptamers tune rPrP 90-231 phase separation. 39,42,50,51 PrP possesses most of the physicochemical characteristics necessary to drive LLPS (Figure 6), including significant levels of intrinsic disorder and capability to interact with NAs.…”

“…39,42,50,51 PrP possesses most of the physicochemical characteristics necessary to drive LLPS ( Figure 6), including significant levels of intrinsic disorder and capability to interact with NAs. 7 In fact, Figure 6 shows that both N-(residues F I G U R E 8 Aptamers tune rPrP 90-231 phase separation. Representative DIC micrographs of rPrP 90-231 :aptamers after 10 minutes incubation at 1:1, 2:1 and 5:1 molar ratios, respectively, in 10 mM Tris (pH 7.4), 100 mM NaCl in presence of A1 (A), A2 (B) or A1_mut (C).…”

“…The precise mechanism of PrP c conversion into PrP Sc and the exact relation of this conversion to the disease pathogenesis remain unknown. 5,7 Different binding affinities and stoichiometries were observed for PrP:NA complexes, depending on the NA size and sequence and on the PrP construct. In contrast, PrP Sc is mainly formed by β-sheets, is insoluble in aqueous solution, and aggregates into species resistant to proteolytic digestion.…”

“…1,2 Mature PrP C is a monomeric protein, susceptible to proteinase K digestion, and harboring an intrinsically disordered N-terminal domain (residues 23 to ~121) and a globular C-terminal domain (residues ~121-231) enriched in α-helices. 7,8 Furthermore, the NA effects on the structure, oligomerization profile, and toxicity of the resultant PrP species to mammalian cells in culture are also variable. 1,2 Although the protein-only hypothesis postulates that PrP Sc is the lone factor responsible for TSE development, 1 in vitro PrP C to PrP Sc conversion assays identified several additional cofactors that may participate in this process.…”

“…5,7 Different binding affinities and stoichiometries were observed for PrP:NA complexes, depending on the NA size and sequence and on the PrP construct. 7,8 Furthermore, the NA effects on the structure, oligomerization profile, and toxicity of the resultant PrP species to mammalian cells in culture are also variable. [9][10][11] Previous reports suggest that DNA ligands with high GC content mediate loss of native secondary structure in recombinant PrP (rPrP), leading to protein aggregation into a cytotoxic species.…”