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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00476143" target="_blank" >RIV/61388963:_____/17:00476143 - isvavai.cz</a>

Result on the web

<a href="http://www.jbc.org/content/292/20/8342.full" target="_blank" >http://www.jbc.org/content/292/20/8342.full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1074/jbc.M117.775924" target="_blank" >10.1074/jbc.M117.775924</a>

Result language

angličtina

Original language name

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

Original language description

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: T-6, T3R3f, and R-6. As there is strong evidence for accumulation of neurotransmitters, such as serotonin and dopamine, in insulin storage granules in pancreatic beta-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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA16-01074S" target="_blank" >GA16-01074S: Beyond the Hofmeister Series: From Molecular Understanding of Specific Ion Effects to their Biological Function</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Biological Chemistry

ISSN

0021-9258

e-ISSN

—

Volume of the periodical

292

Issue of the periodical within the volume

20

Country of publishing house

US - UNITED STATES

Number of pages

14

Pages from-to

8342-8355

UT code for WoS article

000401788600019

EID of the result in the Scopus database

2-s2.0-85019564913