Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation

J Am Chem Soc. 2024 May 22;146(20):13783-13796. doi: 10.1021/jacs.3c14233. Epub 2024 May 9.

Abstract

The deposition of islet amyloid polypeptide (hIAPP) fibrils is a hallmark of β-cell death in type II diabetes. In this study, we employ state-of-the-art MAS solid-state spectroscopy to investigate the previously elusive N-terminal region of hIAPP fibrils, uncovering both rigidity and heterogeneity. Comparative analysis between wild-type hIAPP and a disulfide-deficient variant (hIAPPC2S,C7S) unveils shared fibril core structures yet strikingly distinct dynamics in the N-terminus. Specifically, the variant fibrils exhibit extended β-strand conformations, facilitating surface nucleation. Moreover, our findings illuminate the pivotal roles of specific residues in modulating secondary nucleation rates. These results deepen our understanding of hIAPP fibril assembly and provide critical insights into the molecular mechanisms underpinning type II diabetes, holding promise for future therapeutic strategies.

MeSH terms

  • Amyloid / chemistry
  • Amyloid / metabolism
  • Humans
  • Islet Amyloid Polypeptide* / chemistry
  • Islet Amyloid Polypeptide* / metabolism
  • Protein Conformation