Islet Amyloid Polypeptide (IAPP) is a peptide hormone produced by the pancreatic β-cells along with insulin; IAPP helps to regulate glucose metabolism, but forms amyloid and contributes to β-cell death in type-2 diabetes. Prior work has illustrated that IAPP amyloid fibrils are non-toxic and that an oligomer of IAPP is the toxic species which causes β-cell death. However, the structure and properties of this oligomer are not known; understanding its structure is critical for counteracting β-cell toxicity. In this study, information on the monomer conformational preferences of amyloidogenic human IAPP (h-IAPP) and a non-amyloidogenic IAPP mutant S28P S29P is revealed by the use of time resolved Förster Resonance Energy Transfer (TR-FRET) and Molecular Dynamics (MD) Simulations. Our TR-FRET studies use a very conservative FRET pair (p-cyanophenylalanine and tryptophan) incorporated in different positions of the peptides. Aggregation assays of FRET labeled IAPP versions revealed that incorporation of the FRET pair minimally perturb the toxicity and amyloidogenicity of h-IAPP and the S28P S29P mutant. TR-FRET experiments on both FRET labeled peptides revealed a highly dynamic behavior with dominant extended conformations and several minor compact conformations. MD simulations generated similar distance distributions validating the MD trajectories. The MD simulations revealed that h-IAPP maintains two helical regions in the monomeric form whereas the S28P S29P mutant shows significant reduction in the helical content of the two helical regions. This highlights the importance of helical regions of the peptide for forming the specific toxic oligomeric species of h-IAPP.

Probing fundamental steps in amyloid formation: Investigation of pre-amyloid conformational preferences of toxic human IAPP and non-toxic human IAPP mutants

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