An increasing number of human diseases has been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer's, and Parkinson's, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal that this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and nonamyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a "lipid-chaperone" hypothesis as a unifying framework for protein-membrane poration.

Biophysics and Department of Chemistry University of Michigan Ann Arbor Michigan 48109 1055 United States

Department of Chemical Sciences University of Catania Catania 95124 Italy

Department of Physics University of Helsinki P O Box 64 Helsinki FI 00014 Finland

Heidelberg University Biochemistry Center Heidelberg 69120 Germany

Institute of Organic Chemistry and Biochemistry Prague 160 00 Czech Republic

Istituto di Cristallografia CNR Catania 95126 Italy

J Heyrovský Institute of Physical Chemistry Academy of Sciences of the Czech Republic Prague 117 20 Czech Republic

National Institutes of Health Bethesda Maryland 20892 0001 United States

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Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study