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Alpha-Synuclein Lipid-Dependent Membrane Binding and Translocation through the ?-Hemolysin Channel.
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Biophys J 2014 Feb; 106(3):556-65
Authors: Philip A Gurnev, Thai Leong Yap, Candace M Pfefferkorn, Tatiana K Rostovtseva, Alexander M Berezhkovskii, Jennifer C Lee, V Adrian Parsegian, Sergey M Bezrukov
Gauging the interactions of a natively unfolded Parkinson disease-related protein, alpha-synuclein (?-syn) with membranes and its pathways between and within cells is important for understanding its pathogenesis. Here, to address these questions, we use a robust ?-barrel channel, ?-hemolysin, reconstituted into planar lipid bilayers. Transient, ?95% blockage of the channel current by ?-syn was observed when 1), ?-syn was added from the membrane side where the shorter (stem) part of the channel is exposed; and 2), the applied potential was lower on the side of ?-syn addition. While the on-rate of ?-syn binding to†the channel strongly increased with the applied field, the off-rate displayed a turnover behavior. Statistical analysis suggests that at voltages >50†mV, a significant fraction of the ?-syn molecules bound to the channel undergoes subsequent translocation. The observed on-rate varied by >100 times depending on the bilayer lipid composition. Removal of the last 25 amino acids from the highly negatively charged C-terminal of ?-syn resulted in a significant decrease in the binding rates. Taken together, these results demonstrate that ?-barrel channels may serve as sensitive probes of ?-syn interactions with membranes as well as model systems for studies of channel-assisted protein transport.
PMID: 24507596 [PubMed - as supplied by publisher]