A single-point mutation converts the highly amyloidogenic human islet amyloid polypeptide into a potent fibrillization inhibitor

Aggregation and amyloid formation play critical roles in a range of human diseases including type 2 diabetes. Islet amyloid polypeptide (IAPP or amylin) is responsible for amyloid formation in type 2 diabetes. In vitro, IAPP is one of the most amyloidogenic naturally occurring polypeptide sequences known. Thus the development of effective inhibitors of IAPP amyloid formation is extremely challenging. We demonstrate that a single-point mutant, 12613, converts IAPP from a highly amyloidogenic polypeptide into a potent inhibitor of amyloid formation. The mutant exerts pronounced effects on amyloid fibril formation by wild-type IAPP even at an equimolar ratio. Fluorescence detected thioflavin-T binding assays, circular dichroism, and transmission electron microscopy demonstrate that the 126P inhibits amyloid formation by wild-type IAPP, lengthening the lag phase by almost 20 fold and reducing significantly the amount of aggregated material generated. The potential mode of action of the inhibitor is discussed.