Alpha-synuclein multistate folding thermodynamics: implications for protein misfolding and aggregation.
Alpha-synuclein aggregation has been tightly linked with the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Despite the protein's putative function in presynaptic vesicle regulation, the roles of lipid binding in modulating alpha-synuclein conformations and the aggregation process remain to be fully understood. This study focuses on a detailed thermodynamic characterization of monomeric alpha-synuclein folding in the presence of SDS, a well-studied lipid mimetic. Far-UV CD spectroscopy was employed for detection of conformational transitions induced by SDS, temperature, and pH. The data we present here clearly demonstrate the multistate nature of alpha-synuclein folding, which involves two predominantly alpha-helical partially folded thermodynamic intermediates that we designate as F (most folded) and I (intermediately folded) states. Likely structures of these alpha-synuclein conformational states are also discussed. These partially folded forms can exist in the presence of either monomeric or micellar forms of SDS, which suggests that alpha-synuclein has an intrinsic propensity for adopting multiple alpha-helical structures even in the absence of micelle or membrane binding, a feature that may have implications for its biological activity and toxicity. Additionally, we discuss the relation between alpha-synuclein three-state folding and its aggregation, within the context of isothermal titration calorimetry and transmission electron microscopy measurements of SDS-initiated oligomer formation.
Ferreon
Allan Chris M
AC
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines MB-19, La Jolla, California 92037, USA.
Deniz
Ashok A
AA
D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D044367:Phase Transition; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics; D051844:alpha-Synuclein / Q000737:chemistry*
D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate