Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of -wrapins.
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-wrapins are engineered binding proteins stabilizing the -hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-, and -synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by -wrapins. We show that the multi-targeted, IAPP, amyloid-, and -synuclein, binding properties of -wrapins originate mainly from optimized interactions between -wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous -wrapin target, probably due to the low number of charged residues in the IAPP -hairpin motif. The sub-micromolar affinity of -wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP N-terminal residue Lys1, both located in the flexible N-termini of the interacting proteins. Our findings provide insights towards developing novel protein-based single- or multi-targeted therapeutics.
author list (cited authors)
Orr, A. A., Shaykhalishahi, H., Mirecka, E. A., Jonnalagadda, S., Hoyer, W., & Tamamis, P.
complete list of authors
Orr, Asuka A||Shaykhalishahi, Hamed||Mirecka, Ewa A||Jonnalagadda, Sai Vamshi R||Hoyer, Wolfgang||Tamamis, Phanourios