Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Abstract

Significance There is an enormous interest in the mechanism by which proteins misfold and aggregate into amyloid fibrils. Amyloid has been implicated in many human diseases, but the mechanism of aggregation is not understood. Intermediates have been postulated to play an important role in the process, but there have been very few direct measurements that provide specific structural details. The use of isotope labeling and 2D IR methods has allowed the characterization of a critical intermediate generated during amyloid formation by islet amyloid polypeptide, the peptide responsible for amyloid formation in type 2 diabetes. Identification of this intermediate provides a structural explanation for the lag phase and may explain why some species develop amyloid deposits of hIAPP while others do not.