Structural characterization of alpha-synuclein in an aggregation prone state.
The relation of alpha-synuclein (alphaS) aggregation to Parkinson's disease has long been recognized, but the pathogenic species and its molecular properties have yet to be identified. To obtain insight into the properties of alphaS in an aggregation-prone state, we studied the structural properties of alphaS at acidic pH using NMR spectroscopy and computation. NMR demonstrated that alphaS remains natively unfolded at lower pH, but secondary structure propensities were changed in proximity to acidic residues. The ensemble of conformations of alphaS at acidic pH is characterized by a rigidification and compaction of the Asp and Glu-rich C-terminal region, an increased probability for proximity between the NAC-region and the C-terminal region and a lower probability for interactions between the N- and C-terminal regions.
Cho
Min-Kyu
MK
Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Nodet
Gabrielle
G
Kim
Hai-Young
HY
Jensen
Malene R
MR
Bernado
Pau
P
Fernandez
Claudio O
CO
Becker
Stefan
S
Blackledge
Martin
M
Zweckstetter
Markus
M
D000595:Amino Acid Sequence; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D051844:alpha-Synuclein / Q000737:chemistry*
D051844:alpha-Synuclein