Journal
BIOPHYSICAL JOURNAL
Volume 120, Issue 5, Pages 886-898Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2020.11.2280
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Funding
- FRISBI [ANR-10-INSB-05-02]
- GRAL within the Grenoble Partnership for Structural Biology (PSB) [ANR-10-LABX-49-01]
- Villum Fonden [19175]
- Rhone-Alpes Region
- Fondation RechercheMedicale (FRM)
- FEDER
- Centre National de la Recherche Scientifique (CNRS), CEA, University of Grenoble
- EMBL
- GIS-Infrastructures en Biologie Sante et Agronomie (IBISA)
- JCNS
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This study reveals the crucial role of zinc in insulin dynamics and aggregation kinetics at low pH, where zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein. Introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.
Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment, and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here, we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, in which the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced x-ray emission and x-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.
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