Structural Studies of Truncated Forms of the Prion Protein PrP

Abstract

Prions are proteins that adopt self-propagating aberrant folds. The self-propagating properties of prions are a direct consequence of their distinct structures, making the understanding of these structures and their biophysical interactions fundamental to understanding prions and their related diseases. The insolubility and inherent disorder of prions have made their structures difficult to study, particularly in the case of the infectious form of the mammalian prion protein PrP. Many investigators have therefore preferred to work with peptide fragments of PrP, suggesting that these peptides might serve as structural and functional models for biologically active prions. We have used x-ray fiber diffraction to compare a series of different-sized fragments of PrP, to determine the structural commonalities among the fragments and the biologically active, self-propagating prions. Although all of the peptides studied adopted amyloid conformations, only the larger fragments demonstrated a degree of structural complexity approaching that of PrP. Even these larger fragments did not adopt the prion structure itself with detailed fidelity, and in some cases their structures were radically different from that of pathogenic PrP(Sc).

The part of a long beta hairpin from the scrapie form of the human prion protein is reconstructed in the synthetic CC36 protein

“…The exact molecular mechanism of PrPSc and its plaque formation is still unknown . Several regions of PrPC were shown to be able to form beta sheet in different conditions.…”

“…The length of the first beta strand may be extended under certain conditions. Peptides corresponding to this region are able to form beta sheet with each other …”

“…Short (6–7 amino acid residues in length) synthetic peptides from the second and the third helices connected with each other by the disulfide bond were shown to exist in the form of beta sheet . However, most of the short peptides from the prion protein may somehow form a beta sheet in certain conditions, as well as other short hydrophobic peptides.…”

Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

“…The P102L and P105L mutations also decrease the efficiency of lipid-induced 23-230 recombinant PrP (rPrP) conversion to an infectious PK-resistant form in vitro (7). The P102L substitution in the PrP(89 -143) peptide allows the spontaneous formation of a cross ␤-fibril (8,9), and P102L substitution in 23-231 rPrP is known to reduce the ␣-helical content, suggesting that the P102L substitution has a structural impact (10). However, although the pathogenic potential of the P102L and P105L mutants is evident, Pro-102 and Pro-105 are contained within an intrinsically disordered region of PrP C , and the structural constraints imposed by these proline residues in PrP are not clear.…”

Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure

“…We have recently examined 10 the structures of amyloids formed by a series of fragments of PrP, ranging from the 21-amino-acid fragment PrP21, 11 known to form amyloid fibrils 12 and to be toxic but not self-propagating in cell culture, 13 to the 106-amino-acid fragment PrP Sc 106, which has been shown to support prion propagation in transgenic mice. 14 We compared these structures to that of PrP 27-30 5 ( Fig.…”