Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins. (4th August 2018)

• Record Type: Journal Article
• Authors: Orr, Asuka A.; Shaykhalishahi, Hamed; Mirecka, Ewa A.; Jonnalagadda, Sai Vamshi R.; Hoyer, Wolfgang; Tamamis, Phanourios
• Is Part Of: Computers & chemical engineering. Volume 116(2018)
• Page Start: 322
• Page End: 332
• Publication Date: 2018-08-04
• Subjects: Protein aggregation -- Intrinsically disordered proteins -- α-synuclein -- Amyloid-β -- Amylin -- Molecular dynamics; Chemical engineering -- Data processing -- Periodicals; 660.0285
• DOI: 10.1016/j.compchemeng.2018.02.013
• Languages: English
• ISSNs: 0098-1354

Abstract

Highlights: β-wrapins ΖΑβ3 and AS69, specifically selected for Αβ and α-syn, respectively, bind to IAPP with μM affinities. IAPP is a more promiscuous β-wrapin target, probably due to the lower number of charged residues in its β-hairpin motif compared to Αβ and α-syn. The enhanced affinity of β-wrapin HI18 is achieved in part by a salt-bridge formed between HI18 residue Glu10 and the IAPP N-terminal end. A network of interactions between β-wrapin residues and Αβ, α-syn, and IAPP residues with similar physicochemical properties lead to β-wrapins' multi-targeted binding properties. Abstract: β-wrapins are engineered binding proteins stabilizing the β-hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-β, and α-synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by β-wrapins. We show that the multi-targeted, IAPP, amyloid-β, and α-synuclein, binding properties of β-wrapins originate mainly from optimized interactions between β-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous β-wrapin target, probably due to the low number of charged residues in the IAPP β-hairpin motif. The sub-micromolar affinity of β-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.