Human islet amylin polypeptide (hIAPP) aggregation leads to formation of amyloid plaques causing type 2 diabetes. During aggregation, a cytotoxic transient oligomer is formed that causes beta cell death in the pancreas. Wild-type (WT) oligomers live only for a few minutes during the aggregation process, making it difficult to map the atomic structure. Using 2D IR spectroscopy, we studied the mechanism by which hIAPP aggregates, leading us to develop a mutant that we call “3A” that has oligomer that lives for hours rather than minutes. We established that 3A-hIAPP has a similar oligomeric structure as WT-hIAPP, but a significantly longer lag phase (∼10–12 h) and aggregation time (∼48–72 h). 2D IR data also indicate that 3A oligomeric state remains dominant throughout the course of aggregation. With that mutant in hand, we were able to obtain high-resolution 2D/3D NMR spectra giving the atomic structure of this oligomer. Our structure is the first for hIAPP oligomers, revealing clues to how the structure is linked to hereditary type 2 diabetes. Additionally, simulating the 2D IR spectra of this high-resolution oligomer structure allowed us to decode some of the spectral features that have been misallocated previously demonstrating robustness of our model and technique.
Shivani et al. (Sun,) studied this question.