Skip to main content
U.S. flag

An official website of the United States government

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

Probing Membrane Association of α-Synuclein Domains with VDAC Nanopore Reveals Unexpected Binding Pattern



Daniel Jacobs, David Hoogerheide, Amandine Rovini, Zhiping Jiang, Jennifer C. Lee, Tatiana K. Rostovtseva, Sergey M. Bezrukov


It is well established that α-synuclein (α-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 α-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 α-syn is a strong function of membrane composition and is enhanced by the presence of negatively charged and non-lamellar lipids. Comparison of the nanopore results with those obtained by bilayer overtone and analysis leads to a model of α-syn-membrane interactions involved in the nanomolar-range binding. It assigns lipid-dependent roles to the N- and C-terminal domains of α-sn while accounting for both electrostatic and hydrophobic effects. Notably, the rate of α-syn capture by the pore is not simply proportional to α-syn concentration on the membrane surface but found to be sensitive to the conformation of the α-syn bound state.
Scientific Reports


nanopores, membrane binding affinity, alpha-synuclein, amyloid proteins, single-molecule methods, bilayer overtone analysis, fluorescence correlation spectroscopy


Jacobs, D. , Hoogerheide, D. , Rovini, A. , Jiang, Z. , Lee, J. , Rostovtseva, T. and Bezrukov, S. (2019), Probing Membrane Association of α-Synuclein Domains with VDAC Nanopore Reveals Unexpected Binding Pattern, Scientific Reports, [online], (Accessed April 14, 2024)
Created March 13, 2019, Updated October 12, 2021