Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

Abstract

Prions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrPSc), independently of the nucleotide genome. Therefore, conformational diversity of PrPSc underlies the existence of many prion strains and species barriers of prions, although the conformational information is extremely limited. Interestingly, differences between polymorphic or species-specific residues responsible for the species/strain barriers are often caused by conservative replacements between hydrophobic amino acids. This implies that subtle differences among hydrophobic amino acids are significant for PrPSc structures. Here, we analyzed the influence of different hydrophobic residues on the structures of an in-register parallel {beta}-sheet amyloid of -synuclein (Syn) using molecular dynamics (MD) simulation, and applied the knowledge from the Syn amyloid to modeling a local structure of human PrPSc encompassing residues 107-143. We found that mutations equivalent to polymorphisms that cause transmission barriers substantially affect the stabilities; for example, the G127V mutation, which makes the host resistant to various human prion diseases, greatly destabilized the model amyloid. Our study demonstrates specifically how and in what structures hydrophobic residues can exert unique effects on in-register parallel {beta}-sheet amyloids and provides insights into the molecular mechanism of the strain diversity of prions and other pathogenic amyloids. For Table of Contents Only O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/758938v4_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e55372org.highwire.dtl.DTLVardef@c98952org.highwire.dtl.DTLVardef@1566c06org.highwire.dtl.DTLVardef@ce1945_HPS_FORMAT_FIGEXP M_FIG C_FIG