High-resolution structure of infectious prion protein: the final frontier

Abstract

Prions are the proteinaceous infectious agents responsible for the transmission of prion diseases. The main or sole component of prions is the misfolded prion protein (PrP(Sc)), which is able to template the conversion of the host's natively folded form of the protein (PrP(C)). The detailed mechanism of prion replication and the high-resolution structure of PrP(Sc) are unknown. The currently available information on PrP(Sc) structure comes mostly from low-resolution biophysical techniques, which have resulted in quite divergent models. Recent advances in the production of infectious prions, using very pure recombinant protein, offer new hope for PrP(Sc) structural studies. This review highlights the importance of, challenges for and recent progress toward elucidating the elusive structure of PrP(Sc), arguably the major pending milestone to reach in understanding prions.

Figure 1

Potential roles of non-PrP cofactor molecules during conversion of PrP^C into PrP^Sc. (a) Template-based conversion of PrP^C (blue triangles) into PrP^Sc (red triangles) requires surpassing a large energetic barrier that may preclude efficient misfolding during experimental timescales. In the presence of certain cofactor molecules (red line), the conversion will be greatly enhanced by reduction in the free energy of activation (ΔΔG^‡), as in typical surface-catalyzed chemical reactions. (b) The formation of an infection-competent misfolded PrP conformation depends on permanent binding of a cofactor molecule (blue hexagon) to PrP^Sc, leading to the stabilization of this structure. The resulting complex is able to propagate and produce disease upon in vivo transmission, whereas in the absence of this molecule, PrP^Sc-only aggregates (blue trapezoids) are unable to propagate in vivo.

Figure 2

Alternative models proposed for the structure of PrP^Sc. (a) In the β-helical model, a major refolding of the N-terminal region of PrP27-30 into a β-helix motif from residues 90 to 177 (light green) is proposed. The C-terminal region (residues 178–230, dark green) maintains the α-helical secondary structure organization, as in PrP^C. (b) The β-spiral model developed by molecular dynamics simulation consists of a spiraling core of extended sheets comprising short β-strands, spanning residues 116–119, 129–132, 135–140 and 160–164. In this model, the three α-helices in PrP^C maintain this conformational motif. (c) The parallel in-register extended β-sheet model of PrP^Sc proposes a thorough refolding of PrP^C into a structure composed mainly of β-sheets. To facilitate comparison, the same color assignment for structural motifs has been used in all panels. The figure for the spiral model was kindly provided by W. Chen and V. Daggett.