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Dimerization of transmembrane domain of insulin receptor: structure and possible role in activation

P. 262-262.
Zamaletdinov M. F., Kuznetsov A., Maurice P., Efremov R.

Insulin receptor (IR) family is represented by three membrane proteins participating in organism development, growth, and vital activity. Modulation of the functioning of these receptors by external agents looks very perspective from a pharmaceutical point of view. Although IR is well studied, little is known about the role of its transmembrane (TM) domain in receptor activity. Nowadays, the major model of signal transfer by these receptors describes ligand-triggered conformational changes in the extracellular domain, bringing together TM domains that dimerize. This allows trans-autophosphorylation of intracellular domains followed by activation of secondary messengers. However, the conformation of the TM dimeric state is still unknown. Here, we studied in silico dimerization of TM segments of two closest members of the family: IR and IGF-1R. As a result, TM dimeric structures were predicted. This was done taking into account available structural data on extra- and intracellular parts of the receptors. Inspection of the extracellular segment mobility in the basal state revealed several modes of protein motion, although none of them allow TM domain dimerization. The calculated molecular dynamics of TM helices linked to intracellular domain led to a conclusion about autonomic behavior of the TM domain. Based on this data, the dimerization of TM domains was further simulated without extramembrane parts. The most probable models of TM dimeric structures were predicted and
the free energy of helix-helix association in explicit lipid bilayers was evaluated. Two most energetically favorable models for IR and one for IGF-1R were delineated. Despite the lack of sequence homology, TM segments in both receptors pack in similar parallel dimers, thus suggesting a close activation mechanism.


В книге

Под редакцией: M. Purton. Vol. 9: 44th FEBS Congress, From Molecules to Living Systems, Krakow, Poland, July 6‐11, 2019. Oxford: Wiley, 2019.