Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation

Biochimica et Biophysica Acta - Biomembranes. 2020. Vol. 1862. No. 11. P. 183417.

Kuznetsov A., Zamaletdinov M., Bershatsky Y., Urban A., Bocharova O., Bennasroune A., Maurice P., Bocharov E., Efremov R.

Despite the biological significance of insulin signaling, the molecular mechanisms of activation of the insulin receptor (IR) and other proteins from its family remain elusive. Current hypothesis on signal transduction suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to trans-autophosphorylation and kinase activity in intracellular segments of the receptor. Using NMR spectroscopy, we detected dimerization of isolated TM segments of IR in DPC micelles and observed multiple signals of NH groups of protein backbone possibly corresponding to several dimer conformations. Taking available experimental data as constraints, several atomistic models of dimeric TM domains of IR and insulin-like growth factor 1 (IGF-1R) receptors were elaborated. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of the C-termini of FnIII-3 domains and spatial approaching of TM helices upon insulin-induced receptor activation. In addition, we demonstrated that the intracellular part of the receptor does not impose restrictions on the positioning of TM helices in the membrane. Finally, we used two independent structure prediction methods to generate a series of dimer conformations followed by their 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 their mutants. Based on these data, the ability of several segments from other proteins to functionally replace IR and/or IGF-1R TM domains was explained.

Keywords: membrane receptors, мембранные рецепторы, protein-protein interactions, белок-белковые взаимодействия, transmembrane helices, трансмембранные спирали, bitopic membrane protein, битопные мембранные белки

Publication based on the results of: Methods for the analysis of the supercomputer efficiency, novel parallel algorithms for molecular dynamics calculations and modeling of transport processes in liquids and biomembranes (2020)