The fold of alpha-synuclein fibrils.
The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of alpha-synuclein (alpha-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of alpha-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five beta-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of beta-sheet secondary structure. The data suggest that beta1-strand interacts with beta2, beta2 with beta3, beta3 with beta4, and beta4 with beta5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of approximately 2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed.
Vilar
Marçal
M
The Salk Institute for Biological Studies, North Torrey Pines Road, La Jolla, CA 92037, USA.
Chou
Hui-Ting
HT
Lührs
Thorsten
T
Maji
Samir K
SK
Riek-Loher
Dominique
D
Verel
Rene
R
Manning
Gerard
G
Stahlberg
Henning
H
Riek
Roland
R
D000682:Amyloid / Q000737:chemistry*; D020285:Cryoelectron Microscopy; D041961:Deuterium Exchange Measurement; D046529:Microscopy, Electron, Transmission; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry*
D000682:Amyloid; D051844:alpha-Synuclein