The Dynamic Structure of α‑Synuclein Multimers

α-Synuclein,
a protein that forms ordered aggregates in the
brains of patients with Parkinson’s disease, is intrinsically
disordered in the monomeric state. Several studies, however, suggest
that it can form soluble multimers in vivo that have
significant secondary structure content. A number of studies demonstrate
that α-synuclein can form β-strand-rich oligomers that
are neurotoxic, and recent observations argue for the existence of
soluble helical tetrameric species in cellulo that
do not form toxic aggregates. To gain further insight into the different
types of multimeric states that this protein can adopt, we generated
an ensemble for an α-synuclein construct that contains a 10-residue
N-terminal extension, which forms multimers when isolated from Escherichia coli. Data from NMR chemical shifts and residual
dipolar couplings were used to guide the construction of the ensemble.
Our data suggest that the dominant state of this ensemble is a disordered
monomer, complemented by a small fraction of helical trimers and tetramers.
Interestingly, the ensemble also contains trimeric and tetrameric
oligomers that are rich in β-strand content. These data help
to reconcile seemingly contradictory observations that indicate the
presence of a helical tetramer in cellulo on the
one hand, and a disordered monomer on the other. Furthermore, our
findings are consistent with the notion that the helical tetrameric
state provides a mechanism for storing α-synuclein when the
protein concentration is high, thereby preventing non-membrane-bound
monomers from aggregating.