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Conformational Dynamics of α‑Synuclein during the Interaction with Phospholipid Nanodiscs by Millisecond Hydrogen–Deuterium Exchange Mass Spectrometry
Ist Teil von
Journal of the American Society for Mass Spectrometry, 2021-05, Vol.32 (5), p.1169-1179
Ort / Verlag
United States: American Chemical Society
Erscheinungsjahr
2021
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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.
Sprache
Englisch
Identifikatoren
ISSN: 1044-0305
eISSN: 1879-1123
DOI: 10.1021/jasms.0c00463
Titel-ID: cdi_proquest_miscellaneous_2507668745
Format
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