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J Phys Chem B. 2010 Apr 8;114(13):4615-22. doi: 10.1021/jp908092e.

Tryptophan probes at the alpha-synuclein and membrane interface.

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  • 1Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.


Understanding how environmental factors affect the conformational dynamics of alpha-synuclein (alpha-syn) is of great importance because the accumulation and deposit of aggregated alpha-syn in the brain are intimately connected to Parkinson's disease etiology. Measurements of steady-state and time-resolved fluorescence of single tryptophan-containing alpha-syn variants have revealed distinct phospholipid vesicle and micelle interactions at residues 4, 39, 94, and 125. Our circular dichroism data confirm that Trp mutations do not affect alpha-syn membrane binding properties (apparent association constant K(a)app approximately 1 x 10(7) M(-1) for all synucleins) saturating at an estimated lipid-to-protein molar ratio of 380 or approximately 120 proteins covering approximately 7% of the surface area of an 80 nm diameter vesicle. Fluorophores at positions 4 and 94 are the most sensitive to the lipid bilayer with pronounced spectral blue-shifts (W4: Delta(lambda)max approximately 23 nm; W94: Delta(lambda)max approximately 10 nm) and quantum yield increases (W4, W94: approximately 3 fold), while W39 and W125 remain primarily water-exposed. Time-resolved fluorescence data show that all sites (except W125) have subpopulations that interact with the membrane.

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