Engineered binding proteins to amyloidogenic peptides and proteins
The aggregation of proteins into amyloid fibril deposits is a pathological feature of various diseases, including nearly every major neurodegenerative disease such as Alzheimer and Parkinson. We develop, characterize, and apply engineered binding proteins to amyloid-forming proteins, in order to elucidate and modulate protein aggregation reactions. For this purpose, we employ a wide range of techniques in the area of biophysics, biochemistry, and molecular biology.
Beta-wrapins: Engineered binding proteins to amyloid-forming proteins
We generate small binding proteins, termed beta-wrapins, with affinities for key proteins involved in protein misfolding disorders, including alpha-synuclein (Parkinson), tau (Alzheimer), islet amyloid polypeptide (Type 2 diabetes), and amyloid-beta (Alzheimer). Beta-wrapins inhibit aggregation and toxicity of the target proteins. Beta-wrapins act by interfering with the nucleation of aggregation and shifting the equilibrium to the monomeric, soluble state.
Beta-hairpin motifs for molecular recognition of amyloid-forming proteins
Amyloid-forming proteins locally adopt beta-structure upon binding to beta-wrapins. For example, we have identified a beta-hairpin motif in alpha-synuclein. The beta-hairpin is formed in a sequence region that is critical for pathogenesis of Parkinson disease, containing most of the reported disease-related point mutations.
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