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Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain

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    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 MŠk(CZ) LK11205; GA MŠk(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
    http://www.jbc.org/content/291/40/21234.full

    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

     
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