title: Sequence and membrane determinants of the random coil-helix transition of α-synuclein.
abstract: A random coil-helix transition underlies the association of the presynaptic protein α-synuclein (αS) with curved vesicle membranes to fold Asp2-Ala89 into a continuous helix. To clarify this transition, we examined αS folding cooperativity, helix nucleation and propagation in relation to membrane stabilization and leakage on diverse small unilamellar vesicles. The sequences centering on Phe4 and Tyr39 initiate lipid interactions and the Phe4 region nucleates the helix irrespective of the order of Ser9-Ala89. However, helix propagation is not the sum of individual αS-membrane interactions; it requires non-uniform but balanced sequence distributions of lipid affinities and helix flexibility. The attained helix propagation, like folding cooperativity, depends distinctly on membrane lipid composition and correlates to the degree of αS-conferred membrane stabilization. Contrary to classical coil-helix folding thermodynamics, helix propagation proceeds with a small gain in free energy relative to helix nucleation indicating that its binding enthalpy is expended to compensate a high entropic cost of reducing lipid-packing defects in the curved membrane. Non-saturating lipid conditions or rigidification of the αS helix triggers an increase in small unilamellar vesicle membrane leakage. Thus, αS folding parameters appear highly optimized and closely matched to stabilize and protect its target membrane. Aging-associated changes in lipid and αS concentrations may therefore alter synaptic plasticity and contribute to αS misfolding that culminates in fatal neurodegeneration.
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Sowmya B
authors.initials: SB
authors.lastname: Lokappa
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Jae-Eun
authors.initials: JE
authors.lastname: Suk
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Adithya
authors.initials: A
authors.lastname: Balasubramanian
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Situ
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA. Electronic address: tulmer@usc.edu.
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Ulmer
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008823:Micelles; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008563:Membrane Lipids; D008823:Micelles; D051844:alpha-Synuclein
keywords: NMR spectroscopy; membrane damage; protein folding; protein folding diseases; protein–membrane interaction