Contact-induced structure transformation in transmembrane prion propagation

Abstract

Based on recent experimental evidences of the transmission of prion diseases due to a particular transmembrane form (termed (Ctm)PrP), we propose a theoretical model for the molecular mechanism of such conformational diseases, in which a misfolded (Ctm)PrP induces a similar misfolding of another (Ctm)PrP. Computer simulations are performed to investigate the correlation between folding time and the concentration of misfolded PrP in various processes, including dimerization, trimerization, and cooperative dimerization. By comparing with the experimental correlation curve between incubation time and injected dose of scrapie prions, we conclude that cooperative dimerization may play an important role in the pathological mechanism of prion diseases.

FIGURE 1

The native α-helical conformation (a) and the metastable β-hairpin conformation (b) of the amino-acid sequence HMAGAAAAGA VVGGLGGYML GSAMV.

FIGURE 2

Average hydropathy index of S135V mutated Syrian hamster prion protein (SHaPrP^29-231) for WS = 20, 24, and 25 using the Hopp-Woods hydropathy index. The predicted TM domain is also shown for these three values of WS.

FIGURE 3

Average hydropathy index of S135V mutated Syrian hamster prion protein (SHaPrP^29–231) for WS = 20, 24, and 25 using the Kite-Doolittle hydropathy index. The predicted TM domain is also shown for these three values of WS.

FIGURE 4

Temperature dependence of the chain's helical fraction and MFPT to the ground state for the amino-acid sequence HMAGAAAAGA VVGGLGGYML GSAMV, starting from a random initial configuration.

FIGURE 5

A model of prion disease propagation. The native helical form of a prion misfolds to a β-structure in the presence of the stiff misfolded β-structure form.

FIGURE 6

Structures of model amyloid protofibrils obtained in simulations of three molecules.

FIGURE 7

Comparison of the correlation curves between MFPT and the concentration (C) of misfolded prions for dimerization (open squares), trimerization (open diamonds), cooperative dimerization (solid circles, MFPT; solid stars, 50% death rate), and experimental results from Prusiner et al. (25).

FIGURE 8

The β-dependence of MFPT for a cooperative dimerization of the amino-acid sequence HMAGAAAAGA VVGGLGGYML GSAMV. The initial configuration includes a β-hairpin template and a free α-helical motif.

FIGURE 9

Cumulative distribution of the first passage time for cooperative dimerization at C = 4.04% and 9.15%. One hundred different computer simulations are carried out for each concentration.