TY - JOUR
T1 - Conformational heterogeneity of α-synuclein in membrane
AU - Vermaas, Josh V.
AU - Tajkhorshid, Emad
N1 - Publisher Copyright:
© 2014 Elsevier B.V.
PY - 2014/12
Y1 - 2014/12
N2 - 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. 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 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 its spontaneous 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.
AB - 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. 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 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 its spontaneous 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.
KW - HMMM
KW - Membrane binding
KW - Molecular dynamics
KW - Peripheral membrane protein
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=84925510085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925510085&partnerID=8YFLogxK
U2 - 10.1016/j.bbamem.2014.08.012
DO - 10.1016/j.bbamem.2014.08.012
M3 - Article
C2 - 25135664
AN - SCOPUS:84925510085
VL - 1838
SP - 3107
EP - 3117
JO - Biochimica et Biophysica Acta - Biomembranes
JF - Biochimica et Biophysica Acta - Biomembranes
SN - 0005-2736
IS - 12
ER -