title: Molecular details of α-synuclein membrane association revealed by neutrons and photons.
abstract: α-Synuclein (α-syn) is an abundant neuronal protein associated with Parkinson's disease that is disordered in solution, but it exists in equilibrium between a bent-helix and an elongated-helix on negatively charged membranes. Here, neutron reflectometry (NR) and fluorescence spectroscopy were employed to uncover molecular details of the interaction between α-syn and two anionic lipids, phosphatidic acid (PA) and phosphatidylserine (PS). Both NR and site-specific Trp measurements indicate that penetration depth of α-syn is similar for either PA- or PS-containing membranes (∼9-11 Å from bilayer center) even though there is a preference for α-syn binding to PA. However, closer examination of the individual Trp quenching profiles by brominated lipids reveals differences into local membrane interactions especially at position 39 where conformational heterogeneity was observed. The data also indicate that while W94 penetrates the bilayer as deeply as W4, W94 resides in a more polar surrounding. Taken together, we suggest the N- and C-terminal regions near positions 4 and 94 are anchored to the membrane, while the putative linker spanning residue 39 samples multiple conformations, which are sensitive to the chemical nature of the membrane surface. This flexibility may enable α-syn to bind diverse biomembranes in vivo.
authors: †Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors: Zhiping
authors: Z
authors: Jiang
authors: †Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors: Sara K
authors: SK
authors: Hess
authors: ‡Physics Department, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.|§Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States.
authors: Frank
authors: F
authors: Heinrich
authors: †Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors: Jennifer C
authors: JC
authors: Lee
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D033363:Neutron Diffraction; D010712:Phosphatidic Acids / Q000378:metabolism; D017785:Photons; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010712:Phosphatidic Acids; D051844:alpha-Synuclein