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Roy, D.* ; Chakraborty, S.* ; Suladze, S. ; Kim, M.* ; Chandra Maity, N.* ; Mroue, K.* ; Biswas, R.* ; Reif, B. ; Lee, D.* ; Bhaumik, P.* ; Bhunia, A.*

Generation of membrane-damaging hIAPP oligomers via direct interaction with DOPC/DOPS nanodiscs.

Langmuir 42:9045-9060 (2026)
DOI PMC
The amyloidogenesis of the pancreatic metabolic hormone human islet amyloid polypeptide (hIAPP) is associated with dysfunction of the pancreatic β-cell function in type II diabetes. Although the β-cell membrane is known to play a crucial role in amyloid formation of the hIAPP, the mechanistic understanding of this membrane-mediated process remains largely unclear. Here, using extensive biophysical and simulation experiments, we have investigated the direct interaction between the hIAPP with lipid nanodiscs mimicking the anionic β-cell membrane (7:3 DOPC/DOPS). Our data confirmed that nanodiscs significantly suppressed hIAPP fibrillation by stabilizing the oligomeric conformer. Importantly, these membrane-bound oligomers, rather than mature fibrils, are responsible for membrane disruption, as demonstrated by 31P solid-state NMR and dye leakage assays. Atomistic molecular dynamics (MD) simulations reveal that the initial adsorption is driven by the positively charged N-terminal residues (K1, N3, and R11) of the hIAPP. At acidic pH, representative of secretory granules, the central region (including His18) also contributes to membrane binding. These findings are quantitatively validated by residue-specific NMR chemical shift perturbations and relaxation measurements. Collectively, the result provides a mechanistic insight into how the β-cell membrane catalyzes the formation of toxic hIAPP oligomers, offering an improved therapeutic strategy against type II diabetes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Islet Amyloid Polypeptide; High-affinity Binding; Molecular-mechanisms; Insulin; Proteins; Dynamics; Iapp; Beta; Ph; Gromacs
ISSN (print) / ISBN 0743-7463
e-ISSN 1520-5827
Zeitschrift Langmuir
Quellenangaben Band: 42, Heft: 13, Seiten: , Artikelnummer: 9045-9060 Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen Department of Biotechnology, Ministry of Science and Technology, India
Council of Scientific and Industrial Research, India
University Grants Commission
Deutsche Forschungsgemeinschaft
Seoul National University of Science and Technology