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Site-Specific Fluorescence Dynamics of alpha-Synuclein Fibrils Using Time-Resolved Fluorescence Studies: Effect of Familial Parkinson's Disease-Associated Mutations

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Title Site-Specific Fluorescence Dynamics of alpha-Synuclein Fibrils Using Time-Resolved Fluorescence Studies: Effect of Familial Parkinson's Disease-Associated Mutations
 
Creator SAHAY, S
ANOOP, A
KRISHNAMOORTHY, G
MAJI, SK
 
Subject FREE-ENERGY LANDSCAPES
WILD-TYPE
NEUROTOXICITY
INCLUSIONS
PROTEIN
IMPACT
CELLS
 
Description alpha-Synuclein (alpha-Syn) aggregation is directly implicated in both the initiation and spreading of Parkinson's Diseases (PD) pathogenesis. Although the familial PD-associated mutations (A53T, E46K, and A30P) are known to affect the aggregation kinetics of alpha-Syn in vitro, their structural differences in resultant fibrils are largely unknown. In this report we studied the site-specific dynamics of wild type (wt) alpha-Syn and its three PD mutant fibrils using time-resolved fluorescence intensity, anisotropy decay kinetics, and fluorescence quenching. Our data suggest that the N- and C-terminus are more flexible and exposed compared to the middle non-amyloid-beta component (NAC) region of wt and PD mutant alpha-Syn fibrils. Yet the N-terminus showed great conformational heterogeneity compared to the C-terminus for all these proteins. 71 position of E46K showed more flexibility and solvent exposure compared to other alpha-Syns, whereas both E46K and A53T fibrils possess a more rigid C-terminus compared to wt and A30P. The present data suggest that wt and PD mutant fibrils possess large differences in flexibility and solvent exposure at different positions, which may contribute to their different pathogenicity in PD.
 
Publisher AMER CHEMICAL SOC
 
Date 2014-12-29T05:34:43Z
2014-12-29T05:34:43Z
2014
 
Type Article
 
Identifier BIOCHEMISTRY, 53(5)807-809
0006-2960
http://dx.doi.org/10.1021/bi401543z
http://dspace.library.iitb.ac.in/jspui/handle/100/17206
 
Language English