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Conformational heterogeneity of ?-synuclein in membrane.


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

SUBMITTER: Vermaas JV 

PROVIDER: S-EPMC4194229 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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