TY  - JOUR
AU  - Orr, Asuka A.
AU  - Wördehoff
AU  - Hoyer, Wolfgang
AU  - Tamamis, Phanourios
TI  - Uncovering the Binding and Specificity of β-Wrapins for Amyloid-β and α-Synuclein
JO  - The journal of physical chemistry  / B
VL  - 120
IS  - 50
SN  - 1089-5647
CY  - Washington, DC
PB  - Soc.
M1  - FZJ-2017-01246
SP  - 12781-12794
PY  - 2016
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000390735800001
C6  - pmid:27934063
DO  - DOI:10.1021/acs.jpcb.6b08485
UR  - https://juser.fz-juelich.de/record/827040
ER  -