Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses
| Autor: | Anja Muždalo, Katarína Mitrová, Irena Selicharová, Ondřej Socha, Miloš Buděšínský, Pavlo Potalitsyn, Jelena Radosavljević, Michaela Černeková, Milan Fábry, Martina Chrudinová, Lenka Žáková, Jingjing Lin, Martin Lepšík, Kateřina Hanková, Kateřina Macháčková, Květoslava Mlčochová, Jiří Jiráček, Pavel Hobza, Yevgen P. Yurenko |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
insulin receptor binding medicine.medical_treatment Biochemistry structure-function Receptor tyrosine kinase Receptor IGF Type 1 03 medical and health sciences Protein Domains Insulin-Like Growth Factor II medicine structural biology Humans Abnormalities Multiple Amino Acid Sequence Insulin-Like Growth Factor I Binding site Receptor Nuclear Magnetic Resonance Biomolecular Molecular Biology Growth Disorders hormone analog Binding Sites peptide hormone 030102 biochemistry & molecular biology biology Chemistry Insulin Mutagenesis Cell Biology insulin-like growth factor (IGF) molecular dynamics Receptor Insulin Insulin receptor 030104 developmental biology Protein Structure and Folding Mutation receptor tyrosine kinase biology.protein NMR structure Hormone analog complex mutagenesis receptor autophosphorylation Protein Binding Hormone |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra119.010072 |
| Popis: | Information on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A and have identified several critical residues in binding site 2. However, mutagenesis studies suggest that Ile-A10, Ser-A12, Leu-A13, and Glu-A17 also belong to insulin's site 2. Here, to resolve this discrepancy, we mutated these insulin residues and the equivalent residues in IGFs. Our findings revealed that equivalent mutations in the hormones can result in differential biological effects and that these effects can be receptor-specific. We noted that the insulin positions A10 and A17 are important for its binding to IR-A and IR-B and IGF-1R and that A13 is important only for IR-A and IR-B binding. The IGF-1/IGF-2 positions 51/50 and 54/53 did not appear to play critical roles in receptor binding, but mutations at IGF-1 position 58 and IGF-2 position 57 affected the binding. We propose that IGF-1 Glu-58 interacts with IGF-1R Arg-704 and belongs to IGF-1 site 1, a finding supported by the NMR structure of the less active Asp-58-IGF-1 variant. Computational analyses indicated that the aforementioned mutations can affect internal insulin dynamics and inhibit adoption of a receptor-bound conformation, important for binding to receptor site 1. We provide a molecular model and alternative hypotheses for how the mutated insulin residues affect activity. |
| Databáze: | OpenAIRE |
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