Modification of a Small beta-Barrel Protein, To Give Pseudo-Amyloid Structures, Inhibits Amyloid beta-Peptide Aggregation

作者：Murakoshi Yuko; Takahashi Tsuyoshi^*; Mihara Hisakazu

来源：Chemistry - A European Journal, 2013, 19(14): 4525-4531.

DOI：10.1002/chem.201202762

• aggregation
• Alzheimer%26apos
• s disease
• inhibitors
• peptides
• protein engineering

Aggregation of amyloid -peptide (A) is closely related to the pathogenesis of Alzheimer%26apos;s disease (AD). Although much effort has been devoted to the construction of molecules that inhibit the aggregation of A1-42, high doses are needed for the inhibition of A aggregation in many cases. Previously, we reported that designed green fluorescent protein (GFP) analogues that gives pseudo-A -sheet structures can work as an aggregation inhibitor against A. To further test this design strategy, we constructed protein analogues that mimic A -sheet structures of amyloids by using insulin-like growth factor 2 receptor domain 11 (IGF2R-d11) as a scaffold. A designed protein, named IG11KK, which has a parallel configuration of A-like sheets, can bind more preferentially to oligomeric A1-42 than the monomer. Moreover, IG11KK suppressed the aggregation of A1-42 efficiently, even though lower concentrations of IG11KK than A were used. The aggregation kinetics of A in the presence of the designed proteins revealed that IG11KK can work as an inhibitor not only for the early to middle stages, but also in the latter stage of A aggregation owing to its favorable binding to oligomeric structures of A. The design strategy using -barrel proteins such as IGF2R-d11 and GFP is useful in generating excellent inhibitors of protein misfolding and amyloid formation.

• 出版日期2013-4