0466450 - ÚOCHB 2017 RIV US eng J - Článek v odborném periodiku
Hexnerová, Rozálie - Křížková, Květoslava - Fábry, Milan - Sieglová, Irena - Kedrová, Kateřina - Collinsová, Michaela - Ullrichová, P. - Srb, Pavel - Williams, C. - Crump, M. P. - Tošner, Z. - Jiráček, Jiří - Veverka, Václav - Žáková, Lenka
Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain.
Journal of Biological Chemistry. Roč. 291, č. 40 (2016), s. 21234-21245. ISSN 0021-9258. E-ISSN 1083-351X
Grant CEP: GA ČR GA15-19018S; GA MŠMT(CZ) LK11205; GA MŠMT(CZ) LO1304
Institucionální podpora: RVO:61388963 ; RVO:68378050
Klíčová slova: insulin * IGF-2 * receptor
Kód oboru RIV: CE - Biochemie
Impakt faktor: 4.125, rok: 2016 ; AIS: 1.589, rok: 2016
Web výsledku:
http://www.jbc.org/content/291/40/21234.fullDOI: https://doi.org/10.1074/jbc.M116.741041

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.
Trvalý link: http://hdl.handle.net/11104/0264739