Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F16%3A00461800" target="_blank" >RIV/61388963:_____/16:00461800 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/16:10326791

Result on the web

<a href="http://pubs.acs.org/doi/pdf/10.1021/acs.biochem.6b00140" target="_blank" >http://pubs.acs.org/doi/pdf/10.1021/acs.biochem.6b00140</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.biochem.6b00140" target="_blank" >10.1021/acs.biochem.6b00140</a>

Result language

angličtina

Original language name

Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity

Original language description

Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to IGF-1R and to the isoforms of IR (IRA and IR-B) and specific activation of these receptors. Here, we attempted to probe the impact of IGF-1 and IGF-2 D domains (D-1 and D-II, respectively) and the IGF-2 C domain (C-II) on the receptor specificity of these hormones. For this, we made two types of insulin hybrid analogues: (i) with the C terminus of the insulin A chain extended by the amino acids from the D-I and Du domains and (ii) with the C-terminus of the insulin B chain extended by some amino acids derived from the CH domain. The receptor binding affinities of these analogues and their receptor autophosphorylation potentials were characterized. Our results indicate that the D-I domain has a more negative impact than the D-II domain does on binding to IR, and that the D-I domain Pro-Leu-Lys residues are important factors for a different IRA versus IR-B binding affinity of IGF-1. We also showed that the additions of amino acids that partially "mimic" the C-II domain, to the C-terminus of the insulin B chain, change the binding and autophosphorylation specificity of insulin in favor of the "metabolic" IR-B isoform. This opens new venues for rational enhancement of insulin IR-B specificity by modifications beyond the C-terminus of its B chain.

Czech name

—

Czech description

—

Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CE - Biochemistry

OECD FORD branch

—

Project

<a href="/en/project/GA15-19018S" target="_blank" >GA15-19018S: Towards molecular separation of metabolic and mitogenic effects of insulin and IGF-2</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

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

Name of the periodical

Biochemistry

ISSN

0006-2960

e-ISSN

—

Volume of the periodical

55

Issue of the periodical within the volume

21

Country of publishing house

US - UNITED STATES

Number of pages

11

Pages from-to

2903-2913

UT code for WoS article

000377151100002

EID of the result in the Scopus database

2-s2.0-84973370432