TY - JOUR
T1 - α-synuclein induces both positive mean curvature and negative gaussian curvature in membranes
AU - Braun, Anthony R.
AU - Sevcsik, Eva
AU - Chin, Pamela
AU - Rhoades, Elizabeth
AU - Tristram-Nagle, Stephanie
AU - Sachs, Jonathan N.
PY - 2012/2/8
Y1 - 2012/2/8
N2 - Using a combination of X-ray scattering, fluorescence correlation spectroscopy, coarse-grained molecular dynamics (MD) simulations and potential of mean force calculations, we have explored the membrane remodeling effects of monomeric α-synuclein (αS). Our initial findings from multiple approaches are that αS (1) causes a significant thinning of the bilayer and (2) stabilizes positive mean curvature, such that the maximum principle curvature matches that of synaptic vesicles, αS-induced tubules, and the synthetic lipid vesicles to which the protein binds most tightly. This suggests that αS binding to synaptic vesicles likely stabilizes their intrinsic curvature. We then show that αS induces local negative Gaussian curvature, an effect that occurs in regions of αS shown previously via NMR and corroborated by MD simulation to have significant conformational flexibility. The induction of negative Gaussian curvature, which has implications for all curvature-sensing and curvature-generating amphipathic α-helices, supports a hypothesis that connects helix insertion to fusion and fission of vesicles, processes that have recently been linked to αS function. Then, in an effort to explain these biophysical properties of αS, we promote an intrinsic curvature-field model that recasts long-range protein-protein interactions in terms of the interactions between the local curvature fields generated by lipid-protein complexes.
AB - Using a combination of X-ray scattering, fluorescence correlation spectroscopy, coarse-grained molecular dynamics (MD) simulations and potential of mean force calculations, we have explored the membrane remodeling effects of monomeric α-synuclein (αS). Our initial findings from multiple approaches are that αS (1) causes a significant thinning of the bilayer and (2) stabilizes positive mean curvature, such that the maximum principle curvature matches that of synaptic vesicles, αS-induced tubules, and the synthetic lipid vesicles to which the protein binds most tightly. This suggests that αS binding to synaptic vesicles likely stabilizes their intrinsic curvature. We then show that αS induces local negative Gaussian curvature, an effect that occurs in regions of αS shown previously via NMR and corroborated by MD simulation to have significant conformational flexibility. The induction of negative Gaussian curvature, which has implications for all curvature-sensing and curvature-generating amphipathic α-helices, supports a hypothesis that connects helix insertion to fusion and fission of vesicles, processes that have recently been linked to αS function. Then, in an effort to explain these biophysical properties of αS, we promote an intrinsic curvature-field model that recasts long-range protein-protein interactions in terms of the interactions between the local curvature fields generated by lipid-protein complexes.
UR - http://www.scopus.com/inward/record.url?scp=84856763447&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856763447&partnerID=8YFLogxK
U2 - 10.1021/ja208316h
DO - 10.1021/ja208316h
M3 - Article
C2 - 22211521
AN - SCOPUS:84856763447
SN - 0002-7863
VL - 134
SP - 2613
EP - 2620
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 5
ER -