Abstract
In type 2 diabetes, the formation of islet amyloid consisting of islet amyloid polypeptide (IAPP) is associated with reduction in β-cell mass and contributes to the failure of islet cell transplantation. Rational design of inhibitors of IAPP amyloid formation has therapeutic potential, but is hampered by the lack of structural information on inhibitor complexes of the conformationally flexible, aggregation-prone IAPP. Here we characterize a β-hairpin conformation of IAPP in complex with the engineered binding protein β-wrapin HI18. The β-strands correspond to two amyloidogenic motifs, 12-LANFLVH-18 and 22-NFGAILS-28, which are connected by a turn established around Ser-20. Besides backbone hydrogen bonding, the IAPP:HI18 interaction surface is dominated by non-polar contacts involving hydrophobic side chains of the IAPP β-strands. Apart from monomers, HI18 binds oligomers and fibrils and inhibits IAPP aggregation and toxicity at low substoichiometric concentrations. The IAPP β-hairpin can serve as a molecular recognition motif enabling control of IAPP aggregation.
Highlights
Aberrant protein aggregation into amyloid fibrils occurs in many age related diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Type 2 Diabetes (T2D)[1]
Upon addition of [NA]-HI18 resonance dispersion increases, with several resonances experiencing a downfield shift into the chemical shift region characteristic of β-sheet conformation, indicating that binding to HI18 is coupled to folding of islet amyloid polypeptide (IAPP)
The structure of the IAPP:HI18 complex was determined by high-resolution liquid-state NMR spectroscopy (Fig. 1c and Supplementary Table 1, PDB: 5K5G)
Summary
Aberrant protein aggregation into amyloid fibrils occurs in many age related diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Type 2 Diabetes (T2D)[1]. In T2D, the 37 amio acid residue polypeptide IAPP aggregates into pancreatic islet amyloid deposits[2,3]. To provide structural insight into the inhibition of IAPP amyloid formation, we characterize here the interaction of IAPP with the aggregation inhibitor β-wrapin HI18. The library is based on the scaffold ZAβ3, an affibody protein that sequesters a β-hairpin conformation of the Alzheimer’s disease-associated amyloid-βpeptide (Aβ)[18,19]. We have described a related, multi-specific β-wrapin, AS10, which inhibits aggregation and toxicity of IAPP as well as Aβand the Parkinson’s disease-related protein α-synuclein, and which binds presumably all of these three intrinsically disordered proteins in a β-hairpin conformation[20]. We report the NMR structure of the IAPP:HI18 complex, relate the identified IAPP β-hairpin to previously observed β-hairpins of Aβ19 and α-synuclein[21], and investigate the mechanism of inhibition of IAPP aggregation by HI18
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