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

DOI: 10.1074/jbc.M117.775924 DOI Help

Authors: Vladimír Palivec (Czech Academy of Sciences) , Cristina M. Viola (The University of York) , Mateusz Kozak (Czech Academy of Sciences) , Timothy R. Ganderton (University of York) , Květoslava Křížková (Czech Academy of Sciences) , Johan P. Turkenburg (University of York) , Petra Halušková (Czech Academy of Sciences) , Lenka Žáková (Czech Academy of Sciences) , Jiří Jiráček (Czech Academy of Sciences) , Pavel Jungwirth (Czech Academy of Sciences) , Andrzej M. Brzozowski (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 7864 , 9948

Open Access Open Access

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.

Journal Keywords: crystal structure; dopamine; pancreatic islet; serotonin; vesicles; insulin

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 05/04/2017 10:35


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)