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Structural insights into seeding mechanisms of hIAPP fibril formation.
J. Am. Chem. Soc. 146, 13783-13796 (2024)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Islet Amyloid Polypeptide; N-terminal Region; Molecular-dynamics; Nmr-spectroscopy; Software; Aggregation; Proteins; Protons; Amylin; Identification
ISSN (print) / ISBN
0002-7863
e-ISSN
1520-5126
Quellenangaben
Volume: 146,
Issue: 20,
Pages: 13783-13796
Publisher
American Chemical Society (ACS)
Publishing Place
1155 16th St, Nw, Washington, Dc 20036 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
Helmholtz-Gemeinschaft
German Research Foundation (DFG)
German Research Foundation (DFG)