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The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

preprint
submitted on 06.08.2020 and posted on 07.08.2020 by Michele F. M. Sciacca, Fabio Lolicato, Carmelo Tempra, Federica Scollo, Bikash R. Sahoo, Matthew D. Watson, Sara García-Viñuales, Danilo Milardi, Antonio Raudino, Jennifer C. Lee, Ayyalusamy Ramamoorthy, Carmelo La Rosa

Increasing number of human diseases have 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 this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.

History

Email Address of Submitting Author

clarosa@unict.it

Institution

University of Catania

Country

Italy

ORCID For Submitting Author

0000-0002-7123-5347

Declaration of Conflict of Interest

no conflict of interest

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