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Suladze, S. ; Sustay Martinez, C.* ; Rodriguez Camargo, D.C. ; Engler, J. ; Rodina, N. ; Sarkar, R. ; Zacharias, M.* ; Reif, B.

Structural insights into seeding mechanisms of hIAPP fibril formation.

J. Am. Chem. Soc. 146, 13783-13796 (2024)
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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
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0002-7863
e-ISSN 1520-5126
Journal Journal of the American Chemical Society
Quellenangaben Volume: 146, Issue: 20, Pages: 13783-13796 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503090-001
Grants Helmholtz-Gemeinschaft
German Research Foundation (DFG)
DOI 10.1021/jacs.3c14233
WOS ID 001224839600001
Scopus ID 85192793891
PubMed ID 38723619
Erfassungsdatum 2024-06-11
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