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@ARTICLE{Orr:827040,
author = {Orr, Asuka A. and Wördehoff and Hoyer, Wolfgang and
Tamamis, Phanourios},
title = {{U}ncovering the {B}inding and {S}pecificity of
β-{W}rapins for {A}myloid-β and α-{S}ynuclein},
journal = {The journal of physical chemistry / B},
volume = {120},
number = {50},
issn = {1089-5647},
address = {Washington, DC},
publisher = {Soc.},
reportid = {FZJ-2017-01246},
pages = {12781-12794},
year = {2016},
abstract = {Amyloidogenic proteins amyloid-β peptide (Aβ) and
α-synuclein (α-syn) self-assemble into fibrillar amyloid
deposits, senile plaques and Lewy bodies, pathological
features of Alzheimer’s and Parkinson’s diseases,
respectively. Interestingly, a portion of Alzheimer’s
disease cases also exhibit aggregation of α-syn into Lewy
bodies, and growing evidence also suggests that Aβ and
α-syn oligomers are toxic. Therefore, the simultaneous
inhibition through sequestration of the two amyloidogenic
proteins may constitute a promising therapeutic strategy.
Recently discovered β-wrapin proteins pave the way toward
this direction as they can inhibit the aggregation and
toxicity of both Aβ and α-syn. Here, we used computational
methods, primarily molecular dynamics simulations and free
energy calculations, to shed light into the key
interaction-based commonalities leading to the dual binding
properties of β-wrapins for both amyloidogenic proteins, to
identify which interactions potentially act as switches
diminishing β-wrapins’ binding activity for Aβ/α-syn,
and to examine the binding properties of the current most
potent β-wrapin for Aβ. Our analysis provides insights
into the distinct role of the key determinants leading to
β-wrapin binding to Aβ and α-syn, and suggests that the
Aβ 18VFFAED23 and α-syn 38LYVGSK43 are key domains
determining the binding specificity of a β-wrapin. Our
findings can potentially lead to the discovery of novel
therapeutics for Alzheimer’s and Parkinson’s diseases.},
cin = {ICS-6},
ddc = {530},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000390735800001},
pubmed = {pmid:27934063},
doi = {10.1021/acs.jpcb.6b08485},
url = {https://juser.fz-juelich.de/record/827040},
}