Conformational dynamics of wild type and mutant α-synuclein on membrane surfaces
Abstract
α-Synuclein, a small natively unfolded pre-synaptic protein is the major component of intracellular inclusions that are the pathological hallmarks of Parkinson’s disease (PD). Mutations of α-synuclein (A53T, A30P, E46K) are associated with rare familial early onset PD. The normal function of α-synuclein is thought to involve membrane binding. In addition, the misfolding of the protein is accelerated in presence of lipids. The interaction of wild-type and mutant α-synuclein with lipid bilayers has been examined using supported lipid bilayers and epi-fluorescence microscopy. The membranes contained phosphatidylcholine (PC) and phosphatidic acid (PA), which in the absence of protein mix uniformly. Upon addition of protein a rapid separation was observed into PC-rich and PA-rich regions and the protein was observed to bind more avidly to the PA-rich regions. The effects of pH, ionic strength, protein concentration and anionic lipid concentration were examined. The conditions that yielded the greatest extent of aggregation were not the same as those that yielded the most stable aggregates. The structure of the membrane bound protein and the structure of the solution phase protein were both found to play a role in controlling both the extent of aggregation and the type of aggregates formed. The biological implications of this work are discussed.
Degree
Ph.D.
Advisors
Hovis, Purdue University.
Subject Area
Biochemistry|Biophysics
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