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Unravelling the Conformational Dynamics of a-Synuclein's Folding Pathway By Hydrogen-Deuterium Exchange Mass Spectrometry in the Presence of Phospholipid Nanodiscs

Unravelling the Conformational Dynamics of a-Synuclein's Folding Pathway By Hydrogen-Deuterium Exchange Mass Spectrometry in the Presence of Phospholipid Nanodiscs

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Title: Unravelling the Conformational Dynamics of a-Synuclein's Folding Pathway By Hydrogen-Deuterium Exchange Mass Spectrometry in the Presence of Phospholipid Nanodiscs
Author: Oganesyan, Irina
Abstract: Conformational changes of the -synuclein protein during docking into a phospholipid membrane is suspected to play a central role in neuronal cell death during Parkinsons disease. This intrinsically disordered protein obtains its secondary helical structure through a pathway of transition states. These states, when improperly folded, are prone to stack into hydrophobic -sheets, which later lead to the formation of fibrils and Lewy bodies the hallmarks of Parkinsons. The ability to elucidate key transition intermediates of -synuclein will clarify the mechanism used in the development of this disease and help facilitate the screening of drugs for the treatment of all -synucleinopathies. In this research, Time-Resolved Hydrogen/Deuterium Exchange Mass Spectrometry coupled with the nanodiscs technology as artificial membrane was employed to unravel structural behaviour of this protein in the presence of phospholipid bilayer. As a result, the conformational behaviour of SN indicated rather a transient interaction with phospholipid bilayer than binding to the nanodisc. The key regions of the most structural rearrangements during the interaction with the lipid membrane were identified and were consistent with the published literature. Based on the results of the kinetic HDX studies, the data proposed an evidence for the structural intermediate of SN which was proposed in different theories on SNs conformational behaviour in vivo.
Subject: Chemistry
Keywords: Intrinsically disordered proteins
hydrogen/deuterium exchange mass spectrometry
protein-lipid interaction
nanodisc membrane mimetics
Type: Electronic Thesis or Dissertation
Rights: Author owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
URI: http://hdl.handle.net/10315/35807
Supervisor: Wilson, Derek J
Degree: MSc - Master of Science
Program: Chemistry
Exam date: 2018-08-31
Publish on: 2019-03-05

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