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@ARTICLE{Losasso:201198,
author = {Losasso, Valeria and Pietropaolo, Adriana and Zannoni,
Claudio and Gustincich, Stefano and Carloni, Paolo},
title = {{S}tructural {R}ole of {C}ompensatory {A}mino {A}cid
{R}eplacements in the α-{S}ynuclein {P}rotein},
journal = {Biochemistry},
volume = {50},
number = {32},
issn = {1520-4995},
address = {Columbus, Ohio},
publisher = {American Chemical Society},
reportid = {FZJ-2015-03503},
pages = {6994 - 7001},
year = {2011},
abstract = {A subset of familial Parkinson’s disease (PD) cases is
associated with the presence of disease-causing point
mutations in human α-synuclein [huAS(wt)], including A53T.
Surprisingly, the human neurotoxic amino acid 53T is present
in non-primate, wild-type sequences of α-synucleins,
including that expressed by mice [mAS(wt)]. Because
huAS(A53T) causes neurodegeneration when expressed in
rodents, the amino acid changes between the wild-type human
protein [huAS(wt)] and mAS(wt) might act as intramolecular
suppressors of A53T toxicity in the mouse protein, restoring
its physiological structure and function. The lack of
structural information for mAS(wt) in aqueous solution has
prompted us to conduct a comparative molecular dynamics
study of huAS(wt), huAS(A53T), and mAS(wt) in water at 300
K. The calculations are based on an ensemble of nuclear
magnetic resonance-derived huAS(wt) structures. huAS(A53T)
turns out to be more flexible and less compact than
huAS(wt). Its central (NAC) region, involved in fibril
formation by the protein, is more solvent-exposed than that
of the wild-type protein, in agreement with nuclear magnetic
resonance data. The compactness of mAS(wt) is similar to
that of the human protein. In addition, its NAC region is
less solvent-exposed and more rigid than that of huAS(A53T).
All of these features may be caused by an increase in the
level of intramolecular interactions on passing from
huAS(A53T) to mAS(wt). We conclude that the presence of
“compensatory replacements” in the mouse protein causes
a significant change in the protein relative to huAS(A53T),
restoring features not too dissimilar to those of the human
protein.},
cin = {GRS / IAS-5},
ddc = {570},
cid = {I:(DE-Juel1)GRS-20100316 / I:(DE-Juel1)IAS-5-20120330},
pnm = {899 - ohne Topic (POF2-899)},
pid = {G:(DE-HGF)POF2-899},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000293665500027},
doi = {10.1021/bi2007564},
url = {https://juser.fz-juelich.de/record/201198},
}