Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-40979-8
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Funding
- Intramural Research Program of the National Institutes of Health (NIH)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Heart, Lung, and Blood Institute
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD000072] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL001055] Funding Source: NIH RePORTER
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It is well established that alpha-synuclein (alpha-syn) binding from solution to the surface of membranes composed of negatively charged and/or non-lamellar lipids can be characterized by equilibrium dissociation constants of tens of micromolar. Previously, we have found that a naturally occurring nanopore of the mitochondrial voltage-dependent anion channel (VDAC), reconstituted into planar bilayers of a plant-derived lipid, responds to alpha-syn at nanomolar solution concentrations. Here, using lipid mixtures that mimic the composition of mitochondrial outer membranes, we show that functionally important binding does indeed take place in the nanomolar range. We demonstrate that the voltage-dependent rate at which a membrane-embedded VDAC nanopore captures alpha-syn is a strong function of membrane composition. Comparison of the nanopore results with those obtained by the bilayer overtone analysis of membrane binding demonstrates a pronounced correlation between the two datasets. The stronger the binding, the larger the on-rate, but with some notable exceptions. This leads to a tentative model of alpha-syn-membrane interactions, which assigns different lipid-dependent roles to the N- and C-terminal domains of alpha-syn accounting for both electrostatic and hydrophobic effects. As a result, the rate of alpha-syn capture by the nanopore is not simply proportional to the alpha-syn concentration on the membrane surface but found to be sensitive to the specific interactions of each domain with the membrane and nanopore.
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