Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Mar 24;108(6):1548-1554.
doi: 10.1016/j.bpj.2015.01.008.

Structural Studies of Truncated Forms of the Prion Protein PrP

Affiliations
Free PMC article

Structural Studies of Truncated Forms of the Prion Protein PrP

William Wan et al. Biophys J. .
Free PMC article

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).

Figures

Figure 1
Figure 1
Electron micrographs from amyloid fibrils show that all samples fibrillized. (A) PrP21. (B) PrP55. (C) MoPrP89, refolded in 1 M urea at pH 3. (D) MoPrP89, refolded in 4 M urea at pH 5. (E) BVPrP89, refolded in 1M urea at pH 3. (F) PrPSc106. (G) Sho. Scale bar applies to all panels. Appearances vary because of differences in staining, sources, and electron microscopes, but all samples have clearly fibrillized.
Figure 2
Figure 2
X-ray fiber diffraction patterns from fibers of PrP fragments. (A) PrP21. (B) PrP55 at ∼98% relative humidity. (C) PrP55 at ∼86% relative humidity. (D) MoPrP89 refolded in 1 M urea at pH 3. (E) MoPrP89 refolded in 4 M urea at pH 5. (F) BVPrP89 refolded in 1 M urea at pH 3. (G) PrPSc106. White arrowheads: meridional cross-β diffraction at ∼4.8 Å resolution. Black arrowheads: meridional diffraction at ∼9.6 Å in (A), (B), (C), and (G), and also at ∼6.4 Å in (G). Arrows: equatorial diffraction at 8 to 10 Å in (A), (C), and (D). The inset in (B), which includes the black arrowhead, uses a more intense color table to show the weak meridional intensity at 9.6 Å more clearly. Most panels include sharp crystalline rings from calcite, used as a standard to determine sample-to-detector distance. In (G), diffraction from PrPSc106, the only brain-derived sample, includes many intensities attributed to lipids (7), including an intense meridional intensity at ∼4.2 Å.
Figure 3
Figure 3
X-ray fiber diffraction patterns from fibers of the nonprion protein Shadoo (Sho), which is a paralog of PrP. (A) Mouse Sho. (B) Human Sho. Meridional intensities at ∼9.6 Å (insets, black arrowhead) show that the repeating unit along the filament axis has the thickness of two β-strands. The inserts, which include the black arrowheads, use a more intense color table to show the weak meridional intensities at 9.6 Å more clearly.

Similar articles

See all similar articles

Cited by 11 articles

See all "Cited by" articles

Publication types

Feedback