Normal modes of prion proteins: from native to infectious particle

Abstract

Prion proteins (PrP) are the infectious agent in transmissible spongiform encephalopathies (i.e., mad cow disease). To be infectious, prion proteins must undergo a conformational change involving a decrease in α-helical content along with an increase in β-strand content. This conformational change was evaluated by means of elastic normal modes. Elastic normal modes show a diminution of two α-helices by one and two residues, as well as an extension of two β-strands by three residues each, which could instigate the conformational change. The conformational change occurs in a region that is compatible with immunological studies, and it is observed more frequently in mutant prions that are prone to conversion than in wild-type prions because of differences in their starting structures, which are amplified through normal modes. These findings are valuable for our comprehension of the conversion mechanism associated with the conformational change in prion proteins.

Figure 1. Scaled square displacement of Cα atoms of prion proteins

Shown are the scaled Cα square displacement values of (A) ElNemo and (B) Normod lowest frequency mode of PDB structures 3HAK, 3HAF, 3HEQ, 3HER, and 3HES. The secondary structure is indicated above the residue axis. Note the minimal displacement around helices and sheets.

Figure 2. Lowest frequency mode of prion proteins

Shown in cartoon display are the ensemble structures of the lowest frequency mode of ElNemo of PDB ID 3HAK. Arrows indicate the directions of simultaneous motion in time. Note the elongation of β-strands S1 and S2 (in yellow) which leads to the lengthening of the antiparallel β-sheet“.

Figure 3. Secondary structure probability of the human M129V mutant prion protein

Shown is the probability for helix, sheet, and coil formation of the M129V mutant prion protein (residues 125–174) calculated using NetSurfP (30). The actual secondary structure of PDB ID 3HAK is indicated above the residue axis.

Figure 4. Model of PrP^C isoform and PrP^Sc

Shown are cartoon representations of PrP^C structure, putative PrP^C isoform, and two PrP^Sc models. The PrP^C corresponds to PDB ID 3HAK. The PrP^C isoform is similar to PrP^C with the exception of a β-sheet elongation. PrP^Sc models were based on the trimeric assembly reported by Govaerts et al. (31). In the upper PrP^Sc, the N-terminus adopts a β-helix conformation. In the lower PrP^Sc, the N-terminus adopts a β-sandwich conformation similar to the steric zipper conformation reported by Nelson et al. (36). The figure was prepared using Pymol.