Palivec, Vladimír, Viola, Cristina M, Kozak, Mateusz et al. (8 more authors) (2017) Computational and Structural Evidence for Neurotransmitter-mediated Modulation of the Oligomeric States of Human Insulin in Storage Granules. The Journal of biological chemistry. pp. 8342-8355. ISSN 1083-351X
Abstract
Human insulin is a pivotal protein hormone controlling metabolism, growth and ageing, and whose malfunctioning underlies diabetes, some cancers and neuro-degeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in vitro structures of hexamers of this hormone are available, which fall into three conformational states: T6, T3Rf3 and R6. As there is strong evidence for accumulation of neurotransmitters, such as serotonin and dopamine, in insulin storage granules in pancreatic β-cells, we probed by molecular dynamics (MD) and protein crystallography (PC) if these endogenous ligands affect and stabilize insulin oligomers. Parallel studies independently converged on the observation that serotonin binds well within the insulin hexamer (site I), stabilizing it in the T3R3 conformation. Both methods indicated serotonin binding on the hexamer surface (site III) as well. MD, but not PC, indicated that dopamine was also a good site III ligand. Some of the PC studies also included arginine, which may be abundant in insulin granules upon processing of pro-insulin, and stable T3R3 hexamers loaded with both serotonin and arginine were obtained. The MD and PC results were supported further by in solution spectroscopic studies with R-state specific chromophore. Our results indicate that the T3R3 oligomer is a plausible insulin pancreatic storage form, resulting from its complex interplay with neurotransmitters, and pro-insulin processing products. These findings may have implications for clinical insulin formulations.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2017, The American Society for Biochemistry and Molecular Biology. |
Keywords: | Journal Article |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 01 Jun 2017 12:30 |
Last Modified: | 06 Feb 2025 00:07 |
Published Version: | https://doi.org/10.1074/jbc.M117.775924 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1074/jbc.M117.775924 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:117191 |
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