posted on 2021-03-30, 21:44authored byIrina Oganesyan, Cristina Lento, Anurag Tandon, Derek J. Wilson
Both normal and pathological
functions of α-synuclein (αSN),
an abundant protein in the central and peripheral nervous system,
have been linked to its interaction with membrane lipid bilayers.
The ability to characterize structural transitions of αSN upon
membrane complexation will clarify molecular mechanisms associated
with αSN-linked pathologies, including Parkinson’s disease
(PD), multiple systems atrophy, and other synucleinopathies. In this
work, time-resolved electrospray ionization hydrogen/deuterium exchange
mass spectrometry (TRESI-HDX-MS) was employed to acquire a detailed
picture of αSN’s conformational transitions as it undergoes
complexation with nanodisc membrane mimics with different headgroup
charges (zwitterionic DMPC and negative POPG). Using this approach,
αSN interactions with DMPC nanodiscs were shown to be rapid
exchanging and to have little impact on the αSN conformational
ensemble. Interactions with nanodiscs containing lipids known to promote
amyloidogenesis (e.g., POPG), on the other hand, were observed to
induce substantial and specific changes in the αSN conformational
ensemble. Ultimately, we identify a region corresponding residues
19–28 and 45–57 of the αSN sequence that is uniquely
impacted by interactions with “amyloidogenic” lipid
membranes, supporting the existing “broken-helix” model
for α-synuclein/membrane interactions, but do not detect a “helical
extension” that is also thought to play a role in αSN
aggregation.