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

0461800 - ÚOCHB 2017 RIV US eng J - Článek v odborném periodiku
Křížková, Květoslava - Chrudinová, Martina - Povalová, Anna - Selicharová, Irena - Collinsová, Michaela - Vaněk, Václav - Brzozowski, A. M. - Jiráček, Jiří - Žáková, Lenka
Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity.
Biochemistry. Roč. 55, č. 21 (2016), s. 2903-2913. ISSN 0006-2960
Grant CEP: GA ČR GA15-19018S
Institucionální podpora: RVO:61388963
Klíčová slova: alanine scanning mutagenesis * high-affinity binding * type 1 IGF receptor
Kód oboru RIV: CE - Biochemie
Impakt faktor: 2.938, rok: 2016
http://pubs.acs.org/doi/pdf/10.1021/acs.biochem.6b00140

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.
Trvalý link: http://hdl.handle.net/11104/0261380