Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, ?-Helix to ?-Sheet Transition, and Formation of ?-Barrel Intermediates.

ABSTRACT: The self-assembly of human islet amyloid polypeptide (hIAPP) into ?-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8-17 as ?-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8-20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-? nanofibrils in silico from isolated helical monomers via the helical oligomers and ?-helices to ?-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the ?-to-? transition starts from the hexamers. Converted ?-sheet-rich oligomers first form ?-barrel structures as intermediates before aggregating into cross-? nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of ?-barrel intermediates, and assembly of cross-? protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC6499678 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature