Structural Transformation of Amyloid Peptides Interacting with Lipid Membranes

Abstract

The inherent cytotoxicity of protein aggregates implies a common mechanism for amyloid diseases (Bucciantini et al). However, accumulated evidence suggests that the insoluble fibrils or aggregates are not the culprit. On the other hand, amyloid peptides in soluble form do interact with lipid bilayers, suggesting that the cell plasma membranes are a target of amyloid pathogeneses. In particular, Keyed et al. have demonstrated that amyloid peptides all increase membrane ion conductance without any evidence of discrete channel or pore formation. In this study we try to find the common molecular process of soluble amyloid peptides interacting with lipid membranes that might induce membrane conductivity. It is difficult to study this molecular process for most amyloid peptides because of its propensity to fibrillize at relatively low solution concentration. PrP 106-126 is a random coil in its soluble form. We study its kinetics of structural transformation in the presence of lipid vesicles. The time dependence of the structural changes was analyzed as a function of the lipid concentration. We demonstrate that the soluble peptides transform from random coils to alpha-helices upon binding to lipid bilayers. The helical state is stable, as long as the bound peptide to lipid ratio P/L on the lipid vesicle is below a critical value P/L∗. But as P/L exceeds P/L∗, the peptides transform from the helical state to beta-aggregates. This is consistent with previous studies of penetration and hIAPP in multiple lipid bilayers. Thus we found the common fibrillization process of amyloid peptides interacting with lipid bilayers. Our proposal is that the process of peptides’ transformation from random coils to helices and then to beta-aggregation creates defects in the membranes that allow ion permeation to occur as observed by Keyed et al.