Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 17, Issue 24, Pages 15561-15568Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4cp05883f
Keywords
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Funding
- NSF [CBET 1053857]
- NIH [GM 097552, GM102815, NS084998]
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alpha-Synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson's disease. In neurons, alpha-synuclein is thought to play important roles in mediating both endo-and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of alpha-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by alpha-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of alpha-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of alpha-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of alpha-synuclein on the membrane, revealing a constant area increase induced by the binding per alpha-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for alpha-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of alpha-synuclein's membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by alpha-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie alpha-synuclein's role in mediating cell trafficking processes such as endo-and exocytosis.
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