Conformational heterogeneity of α -synuclein in membrane

Abstract

α-Synuclein (αS) is a natively disordered protein in solution, thought to be involved in the fusion of neurotransmitter vesicles to cellular membranes during neurotransmission. Monomeric αS has been previously characterized in two distinct membrane–associated conformations: a broken-helix structure, and an extended helix. Employing atomistic molecular dynamics and a novel membrane representation with significantly enhanced lipid mobility (HMMM), we investigate the process of spontaneous membrane binding of αS and the conformational dynamics of monomeric αS in its membrane-bound form. By repeatedly placing helical αS monomers in solution above a planar lipid bilayer and observing their spontaneous association and insertion into the membrane during twenty independent unbiased simulations, we are able to characterize αS in its membrane-bound state, suggesting that αS has a highly variable membrane insertion depth at equilibrium. Our simulations also capture two distinct states of αS, the starting broken-helix conformation seen in the micelle bound NMR structures, and a semi-extended helix. Analysis of lipid distributions near αS monomers indicates that the transition to a semi-extended helix is facilitated by concentration of phosphatidyl-serine headgroups along the inner edge of the protein. Such a lipid-mediated transition between helix-turn-helix and extended conformations of αS may also occur in vivo, and may be important for the physiological function of αS.

Conformational Dynamics of the Human Islet Amyloid Polypeptide in a Membrane Environment: Toward the Aggregation Prone Form

“…Given the increased lipid mobility, the model accelerates various membrane-associated phenomena while preserving atomic accuracy of the membrane surface. HMMM membranes have thus been used to successfully capture membrane interaction and insertion of a variety of peripheral proteins, e.g., the GLA domain of the human coagulation factor VII 45 , cytochrome P450 47 , talin 48 , α-synuclein (using a micelle-bound starting structure) 49 , and synaptotagmin. 50 Insertion of phospholipids into the membrane 51 , as well as determining the optimal tilt angle of transmembrane helices, 52 have also been successfully accomplished with this model.…”

Efficient Exploration of Membrane-Associated Phenomena at Atomic Resolution

“…The HMMM representation significantly accelerates lateral lipid diffusion and enhances lipid-protein sampling (Arcario et al, 2011; Ohkubo et al, 2012). A particular strength of this membrane representation is that it affords multiple simulations of spontaneous protein interactions with the membrane in less time than is required to simulate the biased binding of a peripheral protein in a conventional simulation (Ohkubo et al, 2012; Baylon et al, 2013; Vermaas and Tajkhorshid, 2014a; Arcario and Tajkhorshid, 2014), providing for efficient and enhanced sampling of protein-lipid interactions. By design, the kinetics of membrane-associated processes are accelerated by the HMMM model due to faster lipid diffusion.…”

“…The HMMM model has been successfully applied to simulation studies of several membrane-associated protein systems(Ohkubo et al, 2012; Baylon et al, 2013; Vermaas and Tajkhorshid, 2014a; Blanchard et al, 2014; Arcario and Tajkhorshid, 2014; Wu and Schulten, 2014; Rhéault et al, 2015). We begin this review by describing the development trajectory of the HMMM model, followed by a set of its recent applications to a wide variety of membrane-associated phenomena including: phospholipid insertion into membrane (Vermaas and Tajkhorshid, 2014b), binding and insertion of peripheral proteins such as cytochrome P450 (Baylon et al, 2013), hemoglobin N (Rhéault et al, 2015), talin (Arcario and Tajkhorshid, 2014), synaptotagmin I (Wu and Schulten, 2014), and α -synuclein (Vermaas and Tajkhorshid, 2014a), and studies of pre-fusion configuration of synaptobrevin transmembrane helix in a lipid bilayer (Blanchard et al, 2014).…”

Membrane Remodelling Activity of ?-Synuclein

“…The flexible and dynamic nature of α-Syn is also reflected by the fact that multiple binding modes to membranes have been revealed 20,35,36 . The helical conformation adopted by the first 100 amino acid residues of α-Syn upon binding can be extended and uninterrupted 37,38 , or consist of two helices connected by a short loop in a horseshoe-like fold 39,40 .…”