Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F16%3A00466450" target="_blank" >RIV/68378050:_____/16:00466450 - isvavai.cz</a>
Alternative codes found
RIV/61388963:_____/16:00466450 RIV/00216208:11310/16:10329390
Result on the web
<a href="http://www.jbc.org/content/291/40/21234.full" target="_blank" >http://www.jbc.org/content/291/40/21234.full</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1074/jbc.M116.741041" target="_blank" >10.1074/jbc.M116.741041</a>
Alternative languages
Result language
angličtina
Original language name
Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain
Original language description
Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor-specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity toward IR-A, particularly the analogs with a Pro-Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and S29N point mutation. Consequently, this analog has almost a 10-fold higher IGF1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for cost-effective isotope labeling required for a detailedNMRstructural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domains.
Czech name
—
Czech description
—
Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
CE - Biochemistry
OECD FORD branch
—
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Biological Chemistry
ISSN
0021-9258
e-ISSN
—
Volume of the periodical
291
Issue of the periodical within the volume
40
Country of publishing house
US - UNITED STATES
Number of pages
22
Pages from-to
21234-21245
UT code for WoS article
000385406200036
EID of the result in the Scopus database
2-s2.0-84988964112