Exploring Lipid-Dependent Conformations of Membrane-Bound α-Synuclein with the VDAC Nanopore
David Hoogerheide, Tatiana Rostovtseva, Sergey M. Bezrukov
Regulation of VDAC by α-Synuclein (αSyn) is a rich and instructive example of protein-protein interactions catalyzed by a lipid membrane surface. αSyn, a peripheral membrane protein involved in Parkinson's disease pathology, is known to bind to membranes in a transient manner. αSyn's negatively charged C-terminal tail is then available to be electromechanically trapped by the VDAC β-barrel pore, a process that is observed in vitro as the reversible reduction of ion flow through a single voltage-biased VDAC nanopore. Binding of αSyn to the lipid bilayer is a prerequisite of the channel-protein interaction; surprisingly, however, we find that the strength of αSyn binding to the membrane does not correlate in any simple way with its efficiency of blocking VDAC, suggesting that the lipid-dependent conformations of the membrane-bound αSyn control the interaction. Quantitative models of the free energy landscape governing the capture and release processes allow us to discriminate between several αSyn (sub-) conformations on the membrane surface. These results, combined with known structural features of αSyn on anionic lipid membranes, point to a model in which the lipid composition determines the fraction of αSyn molecules for which the charged C terminal domain is constrained to be close, but not tightly bound, to the membrane surface and thus readily captured by VDAC nanopore. We speculate that changes in the mitochondrial membrane lipid composition may be key regulators of the αSyn-VDAC interaction and consequently of VDAC-facilitated transport of ions and metabolites in and out of mitochondria and, therefore, mitochondrial metabolism.
, Rostovtseva, T.
and Bezrukov, S.
Exploring Lipid-Dependent Conformations of Membrane-Bound α-Synuclein with the VDAC Nanopore, BBA - Biomembranes
(Accessed December 10, 2023)