Record Details

Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of alpha-Synuclein

DSpace at IIT Bombay

View Archive Info
 
 
Field Value
 
Title Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of alpha-Synuclein
 
Creator SAHAY, S
GHOSH, D
DWIVEDI, S
ANOOP, A
MOHITE, GM
KOMBRABAIL, M
KRISHNAMOORTHY, G
MAJI, SK
 
Subject TIME-RESOLVED FLUORESCENCE
PHOTOINDUCED CROSS-LINKING
AMYLOID FIBRIL FORMATION
FREE-ENERGY LANDSCAPES
IN-VITRO
TRYPTOPHAN FLUORESCENCE
E46K MUTATION
LEWY BODIES
WILD-TYPE
NEURON DEATH
-Synuclein
Amyloid
Fluorescence Anisotropy
Parkinson Disease
Protein Aggregation
Protein Misfolding
 
Description Background: Aggregation of -Syn is associated with PD pathogenesis. Results: Despite being natively unfolded, a site-specific structure exists in -Syn that is significantly altered by familial PD-associated E46K, A53T, and A30P mutations. Conclusion: Altered site-specific structure of the PD-associated mutants may attribute to their different aggregation propensity. Significance: This study contributes to understanding the relationship between structure and aggregation of -Syn. Human -synuclein (-Syn) is a natively unstructured protein whose aggregation into amyloid fibrils is associated with Parkinson disease (PD) pathogenesis. Mutations of -Syn, E46K, A53T, and A30P, have been linked to the familial form of PD. In vitro aggregation studies suggest that increased propensity to form non-fibrillar oligomers is the shared property of these familial PD-associated mutants. However, the structural basis of the altered aggregation propensities of these PD-associated mutants is not yet clear. To understand this, we studied the site-specific structural dynamics of wild type (WT) -Syn and its three PD mutants (A53T, E46K, and A30P). Tryptophan (Trp) was substituted at the N terminus, central hydrophobic region, and C terminus of all -Syns. Using various biophysical techniques including time-resolved fluorescence studies, we show that irrespective of similar secondary structure and early oligomerization propensities, familial PD-associated mutations alter the site-specific microenvironment, solvent exposure, and conformational flexibility of the protein. Our results further show that the common structural feature of the three PD-associated mutants is more compact and rigid sites at their N and C termini compared with WT -Syn that may facilitate the formation of a partially folded intermediate that eventually leads to their increased oligomerization propensities.
 
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
 
Date 2016-01-15T07:51:52Z
2016-01-15T07:51:52Z
2015
 
Type Article
 
Identifier JOURNAL OF BIOLOGICAL CHEMISTRY, 290(12)7804-7822
0021-9258
1083-351X
http://dx.doi.org/10.1074/jbc.M114.598607
http://dspace.library.iitb.ac.in/jspui/handle/100/18096
 
Language en