A topological model of the interaction between alpha-synuclein and sodium dodecyl sulfate micelles.
Human alpha-synuclein is a 140-amino acid protein of unknown function abundantly expressed in the brain and found in Lewy bodies, a characteristic feature of Parkinson's disease. Alpha-synuclein is random in water under physiological conditions, but the first approximately 100 residues interact with SDS micelles or acidic phospholipid small unilamellar vesicles and adopt an ordered conformation. The rest of the molecule remains disordered in the bulk of the solution. The conformation of the N-terminal portion of the molecule in lipids was described as an extended helix [Ramakrishnan, M., Jensen, P. H., and Marsh, D. (2003) Biochemistry 42, 12919-12926], as two distinct alpha-helices interrupted by a two-residue break [Chandra, S., Chen, X., Rizo, J., Jahn, R., and Sudhof, T. C. (2003) J. Biol. Chem. 278, 15313-15318], or as a noncanonical conformation, the alpha11/3 helix [Bussell, R., Jr., and Eliezer, D. (2003) J. Mol. Biol. 329, 763-778]. We characterized the topology of the different regions of alpha-synuclein relative to the surface of SDS micelles using spin probe-induced broadening of NMR signals, (15)N relaxation measurements, and fluorescence spectroscopy. Our results support the presence of two N-terminal helices, positioned on the surface of the micelle and separated by a flexible stretch. The region of residues 61-95 of the protein also adopts a helical conformation, but it is partially embedded in the micelle. These results could shed some light on the role of the membrane on the aggregation process of alpha-synuclein.
Bisaglia
Marco
M
Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy.
Tessari
Isabella
I
Pinato
Luca
L
Bellanda
Massimo
M
Giraudo
Sabrina
S
Fasano
Mauro
M
Bergantino
Elisabetta
E
Bubacco
Luigi
L
Mammi
Stefano
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D003902:Detergents; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry; D010743:Phospholipids; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate; D051843:Synucleins; D051844:alpha-Synuclein
D003902:Detergents; D008823:Micelles; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010743:Phospholipids; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate