Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation

Saba Suladze, Christian Sustay Martinez, Diana C. Rodriguez Camargo, Jonas Engler, Natalia Rodina, Riddhiman Sarkar, Martin Zacharias, Bernd Reif

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)13783-13796
Number of pages14
JournalJournal of the American Chemical Society
Volume146
Issue number20
DOIs
StatePublished - 22 May 2024
Externally publishedYes

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