title: Insight into α-synuclein plasticity and misfolding from differential micelle binding.
abstract: Misfolded species of the 140-residue protein α-synuclein (αS) are implicated in the demise of dopaminergic neurons, resulting in fatal neurodegeneration. The intrinsically unstructured protein binds curved synaptic vesicle membranes in helical conformations but misfolds into amyloid fibrils via β-sheet interactions. Breaks in helical αS conformation may offer a pathway to transition from helical to sheet conformation. Here, we explore the evolution of broken αS helix conformations formed in complex with SDS and SLAS micelles by molecular dynamics simulations. The population distribution of experimentally observed αS conformations is related to the spatial concentration of intrinsic micelle shape perturbations. For the success of micelle-induced αS folding, we posit the length of the first helical segment formed, which controls micelle ellipticity, to be a key determinant. The degree of micelle curvature relates to the arrangement and segmental motions of helical secondary structure elements. A criterion for assessing the reproduction of such intermediate time scale protein dynamics is introduced by comparing the sampling of experimental and simulated spin label distributions. Finally, at the sites of breaks in the elongated, marginally stable αS helix, vulnerability to forming a transient, intramolecular β-sheet is identified. Upon subsequent intermolecular β-sheet pairing, pathological αS amyloid formation from initial helical conformation is thus achievable.
authors: Department of Biochemistry & Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California , 1501 San Pablo Street, Los Angeles, California 90033, United States.
authors: Parichita
authors: P
authors: Mazumder
authors: Jae-Eun
authors: JE
authors: Suk
authors: Tobias S
authors: TS
authors: Ulmer
mesh_terms: D004058:Diffusion; D008823:Micelles; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013113:Spin Labels; D013997:Time Factors; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D008823:Micelles; D013113:Spin Labels; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate
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