Mar 30, 2017

Computational and structural evidence for neurotransmitter-mediated modulation of the oligomeric states of human insulin in storage granules

The Journal of Biological Chemistry
Vladimír PalivecAndrzej M Brzozowski

Abstract

Human insulin is a pivotal protein hormone controlling metabolism, growth, and aging and whose malfunctioning underlies diabetes, some cancers, and neurodegeneration. 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 and 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 serot...Continue Reading

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Citations

Mentioned in this Paper

Metabolic Process, Cellular
Molecular Dynamics
In Silico
Study
In Vivo
Chromophore
Positioning Attribute
Laboratory Studies
Abnormal Degeneration
Structure of Beta Cell of Islet

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