Conformational properties of alpha-synuclein in its free and lipid-associated states.
alpha-Synuclein (alphaS) is a presynaptic terminal protein that is believed to play an important role in the pathogenesis of Parkinson's disease (PD). We have used NMR spectroscopy to characterize the conformational properties of alphaS in solution as a free monomer and when bound to lipid vesicles and lipid-mimetic detergent micelles. Free wild-type alphaS is largely unfolded in solution, but exhibits a region with a preference for helical conformations that may be important in the aggregation of alphaS into fibrils. The N-terminal region of alphaS binds to synthetic lipid vesicles and detergent micelles in vitro and adopts a highly helical conformation, consistent with predictions based on sequence analysis. The C-terminal part of the protein does not associate with either vesicles or micelles, remaining free and unfolded. These results suggest that one function of alphaS may be to tether as of yet unidentified partners to lipid surfaces via interactions with its C-terminal tail.
Eliezer
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D
Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York, NY, 10021, USA. dae2005@mail.med.cornell.edu
Kutluay
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E
Bussell
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Browne
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G
D002244:Carbon / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D050356:Lipid Metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D010300:Parkinson Disease; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011522:Protons; D012967:Sodium Dodecyl Sulfate / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D008081:Liposomes; D008823:Micelles; D009419:Nerve Tissue Proteins; D011522:Protons; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate; D002244:Carbon; D009584:Nitrogen