The prion protein has DNA strand transfer properties similar to retroviral nucleocapsid protein 1 1Edited by J. Karn

Gabus, Caroline; Auxilien, Sylvie; Péchoux, Christine; Dormont, Dominique; Świętnicki, Wiesław; Morillas, Manuel; Surewicz, Witold K.; Nandi, P. K.; Darlix, Jean Luc

doi:10.1006/jmbi.2001.4544

Cited by 118 publications

(118 citation statements)

References 49 publications

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“…Further studies are required to distinguish between these possibilities and to identify the specific endogenous polyanions that facilitate prion propagation in vivo. Several classes of negatively charged macromolecules could potentially serve as cofactors for prion propagation, including: nucleic acids (17,(32)(33)(34)(35)(36)(37)(38), glycosaminoglycans (14-16), phospholipid-rich membranes (39)(40)(41)(42), and chaperone proteins (43). Interestingly, it has been proposed that polyanions could play a broad role in protein folding and misfolding, and the ability of polyanions to facilitate prion conversion may represent a specific example of that general concept (44).…”

Section: Discussionmentioning

confidence: 99%

Formation of native prions from minimal components in vitro

Deleault¹,

Harris²,

Rees³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

578

635

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The conformational change of a host protein, PrP C , into a disease-associated isoform, PrP Sc , appears to play a critical role in the pathogenesis of prion diseases such as Creutzfeldt–Jakob disease and scrapie. However, the fundamental mechanism by which infectious prions are produced in neurons remains unknown. To investigate the mechanism of prion formation biochemically, we conducted a series of experiments using the protein misfolding cyclic amplification (PMCA) technique with a preparation containing only native PrP C and copurified lipid molecules. These experiments showed that successful PMCA propagation of PrP Sc molecules in a purified system requires accessory polyanion molecules. In addition, we found that PrP Sc molecules could be formed de novo from these defined components in the absence of preexisting prions. Inoculation of samples containing either prion-seeded or spontaneously generated PrP Sc molecules into hamsters caused scrapie, which was transmissible on second passage. These results show that prions able to infect wild-type hamsters can be formed from a minimal set of components including native PrP C molecules, copurified lipid molecules, and a synthetic polyanion.

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Section: Discussionmentioning

confidence: 99%

Formation of native prions from minimal components in vitro

Deleault¹,

Harris²,

Rees³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

578

635

View full text Add to dashboard Cite

show abstract

“…These properties should be investigated further in order to gain more insight into the putative physiological role of PrP in RNA metabolism (25,26,28) and should provide ways to trap PrP in a disease-inactive conformation that might cleanse physiological fluids. …”

Section: Discussionmentioning

confidence: 99%

“…Large and small nucleic acids (21)(22)(23)(24) also interact with PrP. It has been shown that human, ovine, and murine PrPs possess nucleic acid binding and chaperoning activities similar to retroviral nucleocapsid protein (25,26), and these properties are associated with the unstructured N-terminal region of the protein (5,10). Previously reported 2Ј-OH aptamers raised against recombinant hamster prion protein bound to a site between residues 23-52 within this nonspecific nucleic acid binding region (27).…”

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confidence: 99%

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Characterization of 2′-Fluoro-RNA Aptamers That Bind Preferentially to Disease-associated Conformations of Prion Protein and Inhibit Conversion

Rhie

Kirby

Sayer

et al. 2003

Journal of Biological Chemistry

170

148

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We have isolated artificial ligands or aptamers for infectious prions in order to investigate conformational aspects of prion pathogenesis. The aptamers are 2 -fluoro-modified RNA produced by in vitro selection from a large, randomized library. One of these ligands (aptamer SAF-93) had more than 10-fold higher affinity for PrP Sc than for recombinant PrP C and inhibited the accumulation of PrP res in near physiological cell-free conversion assay. To understand the molecular basis of these properties and to distinguish specific from nonspecific aptamer-PrP interactions, we studied deletion mutants of bovine PrP in denatured, ␣-helix-rich and ␤-sheet-rich forms. We provide evidence that, like scrapie-associated fibrils (SAF), the ␤-oligomer of PrP bound to SAF-93 with at least 10-fold higher affinity than did the ␣-form. This differential affinity could be explained by the existence of two binding sites within the PrP molecule. Site 1 lies within residues 23-110 in the unstructured N terminus and is a nonspecific RNA binding site found in all forms of PrP. The region between residue 90 and 110 forms a hinge region that is occluded in the ␣-rich form of PrP but becomes exposed in the denatured form of PrP. Site 2 lies in the region C-terminal of residue 110. This site is ␤-sheet conformation-specific and is not recognized by control RNAs. Taken together, these data provide for the first time a specific ligand for a disease conformation-associated site in a region of PrP critical for conformational conversion. This aptamer could provide tools for the further analysis of the processes of PrP misfolding during prion disease and leads for the development of diagnostic and therapeutic approaches to TSEs.

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“…80 Expression of PrP c in 293T cells impaired HIV-1 production at the post-transcriptional level, especially processing of Env and Vpr. 81 By reducing Env incorporation into the virion, PrP c decreased infectivity efficiency of the produced virion.…”

Section: Prospectsmentioning

confidence: 99%