Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00498603" target="_blank" >RIV/61388963:_____/18:00498603 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/18:10383285

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jpcb.8b06557" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jpcb.8b06557</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jpcb.8b06557" target="_blank" >10.1021/acs.jpcb.8b06557</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

Popis výsledku v původním jazyce

The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of beta-cell storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerization is investigated independently by protein crystallography, molecular dynamics simulations, and capillary electrophoresis. The combined results point to a strong effect of ionic strength on insulin assembly. Molecular simulations and electrophoretic measurements at low/mM salt concentrations show no significant effect of arginine on insulin aggregation. In contrast, crystallographic data at high/molar ionic strength indicate inhibition of insulin hexamerization by arginine due to its binding at the site relevant for intermolecular contacts, which was also observed in MD simulations. Our results thus bracket the in vivo situation in pancreatic, beta-cell storage granules, where the ionic strength is estimated to be in the hundreds of millimolar to submolar range. The present findings add to a molecular understanding of in vivo insulin oligomerization and storage, with additional implications for insulin stability in arginine-rich injections.

Název v anglickém jazyce

Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

Popis výsledku anglicky

The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of beta-cell storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerization is investigated independently by protein crystallography, molecular dynamics simulations, and capillary electrophoresis. The combined results point to a strong effect of ionic strength on insulin assembly. Molecular simulations and electrophoretic measurements at low/mM salt concentrations show no significant effect of arginine on insulin aggregation. In contrast, crystallographic data at high/molar ionic strength indicate inhibition of insulin hexamerization by arginine due to its binding at the site relevant for intermolecular contacts, which was also observed in MD simulations. Our results thus bracket the in vivo situation in pancreatic, beta-cell storage granules, where the ionic strength is estimated to be in the hundreds of millimolar to submolar range. The present findings add to a molecular understanding of in vivo insulin oligomerization and storage, with additional implications for insulin stability in arginine-rich injections.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/EF16_019%2F0000729" target="_blank" >EF16_019/0000729: Chemická biologie pro vývoj nových terapií</a><br>

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Journal of Physical Chemistry B

ISSN

1520-6106

e-ISSN

—

Svazek periodika

122

Číslo periodika v rámci svazku

44

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

10069-10076

Kód UT WoS článku

000449888800001

EID výsledku v databázi Scopus

2-s2.0-85053213595