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Статья

Insulin and IGF-1 receptors transmembrane domain dimers: structure prediction and possible role in activation

FEBS Open Bio. 2021. Vol. 11. No. Suppl.1. P. 219-219.
Kuznetsov A., Bennasroune A., Maurice P., Bershatsky Y., Bocharov E. V., Efremov R.

The receptor tyrosine kinase (RTK) superfamily comprises many different cell-surface receptors having similar membrane organization and function with signal transduction occuring in the dimeric state. Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) differ from other RTKs being constitutively homodimeric transmembrane glycoproteins, and molecular mechanisms of their activation still remain elusive. Current hypothesis suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to kinase activity in intracellular segments of the receptor. Using experimental data as constraints, we proposed several atomistic models of dimeric states of IR and IGF-1R TM domains. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of its C-termini corresponding to spatial approaching of the following TM helices. Also, we demonstrated that the juxtamembrane part of the IR does not impose strong restrictions on the positioning of TM helices. Finally, we utilized two independent structure prediction methods to generate a series of TM dimer conformations followed by cluster analysis and dimerization free energy estimation to select the best dimer models. Biological relevance of the later was further tested via comparison of the hydrophobic organization of TM helices for both wild-type receptors and two their mutants. Based on these data, the role of several TM segments from other proteins in activation of IR and/or IGF-1R was explained. The elaborated models can be used for rational design of new factors modulating insulin signaling.