Journal Article

FZJ-2017-01246

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Uncovering the Binding and Specificity of β-Wrapins for Amyloid-β and α-Synuclein

Orr, A. A. ; Wördehoff ; Hoyer, W.FZJ* ; Tamamis, P. (Corresponding author)

2016
Soc. Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jpcb.6b08485

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.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2016

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Database coverage:
; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; No Authors Fulltext ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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