Structural transformation and aggregation of human alpha-synuclein in trifluoroethanol: non-amyloid component sequence is essential and beta-sheet formation is prerequisite to aggregation.
Amyloid-like aggregation of alpha-synuclein and deposit in Lewy bodies are thought to be the major cause of Parkinson's disease. Here we describe the secondary structural transformation and aggregation of human alpha-synuclein and its C-terminus truncated fragments in trifluoroethanol. Proteins containing the NAC (non-amyloid component) segment undergo a three-state transition: from native random coil to beta-sheet and to alpha-helical structure, while the NAC deficient fragment and gamma-synuclein undergo a typical two-state coil-to-alpha transition. The beta-sheet form is highly hydrophobic that strongly binds to 1-anilinonaphthalene-8-sulfonic acid (ANS) and is prone to self-aggregation. The results suggest that the NAC sequence is essential to beta-sheet formation and the aggregation originates from the beta-sheet intermediate, which may be implicated in the pathogenesis of Parkinson's disease.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, People's Republic of China.
Hong-Tao
HT
Li
Hai-Ning
HN
Du
Lin
L
Tang
Jun
J
Hu
Hong-Yu
HY
Hu
D001704:Biopolymers / Q000737:chemistry; D002942:Circular Dichroism; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010300:Parkinson Disease / Q000209:etiology; D010446:Peptide Fragments / Q000737:chemistry; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D051843:Synucleins; D014270:Trifluoroethanol; D051844:alpha-Synuclein; D051845:gamma-Synuclein
D001704:Biopolymers; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein; D014270:Trifluoroethanol