<p>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.<b></b></p>
Figure 1.1. The cell membrane is a fluid mosaic model. The phospholipid bilayer comprises many different molecular components, including a variety of lipids, proteins, and cholesterol, some of which are with carbohydrate groups attached. This "fluid lipid sea" hosts other molecules such as membrane proteins 1,2,13 . This illustration is licensed under the Creative Commons Attribution 4.
<p>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.<b></b></p>
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