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McCalpin, S.D.* ; Khemtemourian, L.* ; Suladze, S. ; Ivanova, M.I.* ; Reif, B. ; Ramamoorthy, A.*

Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide.

Comm. Biol. 7:776 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D. Here, we describe the combined ability of low pH, zinc, and insulin to inhibit hIAPP fibrillation. Insulin dose-dependently slows hIAPP aggregation near neutral pH but had less effect on the aggregation kinetics at acidic pH. We determine that insulin alters hIAPP aggregation in two manners. First, insulin diverts the aggregation pathway to large nonfibrillar aggregates with ThT-positive molecular structure, rather than to amyloid fibrils. Second, soluble insulin suppresses hIAPP dimer formation, which is an important early aggregation event. Further, we observe that zinc significantly modulates the inhibition of hIAPP aggregation by insulin. We hypothesize that this effect arose from controlling the oligomeric state of insulin and show that hIAPP interacts more strongly with monomeric than oligomeric insulin.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Fibril Formation; Iapp; Protein; Peptides; Mechanism; Amyloidogenesis; Oligomers; Amylin; Complexes; Pathways
ISSN (print) / ISBN 2399-3642
e-ISSN 2399-3642
Zeitschrift Communications Biology
Quellenangaben Band: 7, Heft: 1, Seiten: , Artikelnummer: 776 Supplement: ,
Verlag Springer
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen NIH