Solid-state NMR reveals structural differences between fibrils of wild-type and disease-related A53T mutant alpha-synuclein.
Fibrils from the Parkinson's-disease-related A53T mutant of alpha-synuclein were investigated by solid-state NMR spectroscopy, electron microscopy, and atomic force microscopy. Sequential solid-state NMR resonance assignments were obtained for a large fraction of the fibril core. Experiments conducted above and below the freezing point suggest that the fibrils contain regions with increased mobility and structural elements different from beta-strand character, in addition to the rigid beta-sheet-rich core region. As in earlier studies on wild-type alpha-synuclein, the C-terminus was found to be flexible and unfolded, whereas the main core region was highly rigid and rich in beta-sheets. Compared to fibrils from wild-type alpha-synuclein, the well-ordered beta-sheet region extends to at least L38 and L100. These results demonstrate that a disease-related mutant of alpha-synuclein differs in both aggregation kinetics and fibril structure.
Heise
Henrike
H
Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Solid-State NMR Group, Am Fassberg 11, D-37077 Göttingen, Germany. h.heise@fz-juelich.de
Celej
M Soledad
MS
Becker
Stefan
S
Riedel
Dietmar
D
Pelah
Avishay
A
Kumar
Ashutosh
A
Jovin
Thomas M
TM
Baldus
Marc
M
D000595:Amino Acid Sequence; D004926:Escherichia coli / Q000235:genetics; D005615:Freezing; D006801:Humans; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
D011994:Recombinant Proteins; D051844:alpha-Synuclein