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Structural basis of the signal transduction via transmembrane domains of type I receptors in norma and pathology

P. 130-130.
Bocharov E. V., Lesovoy D. M., Pavlov K., Bocharova O. V., Urban A. S., Mineev K. S., Bershacky Y., Shtykova E., Volynsky P. E., Efremov R., Arseniev A. S.

The human epidermal growth factor (EGFR/HER) and growth hormone (GHR) receptors serve as excellent models of type I receptors to illustrate how ligand-induced conformational rearrangements and specific dimerization of extracellular domains lead to the allosteric activation of the cytoplasmic domains via single-span transmembrane domain (TMD). We determined the alternative dimeric conformations of the EGFR and GHR TMDs in different membrane-mimicking environments using high-resolution NMR spectroscopy combined with MD-relaxation in explicit lipid bilayer. Based on the location of pathogenic transmembrane mutations, observed conformations correspond to the dormant and active states of both receptors, assuming an impact of intramembrane interactions to the cell signaling dysfunction in human organism. Fine adaptation of intermolecular polar and hydrophobic contacts that we found to accompany the different EGFR TMD dimerizations suggests that certain membrane properties can govern the TMD helix-helix packing and, thus, their alteration can trigger the receptor state. Whereas two distinct dimeric modes of GHR TMD revealed the functional role of juxtamembrane region rearrangements in alternation between protein-protein and protein-lipid interactions that can be initiated by ligand binding. Observed the TMD helix-helix packing diversity appears in favor of the lipid-mediated rotationcoupled activation mechanism, which implies that the sequence of structural rearrangements of EGFR and GHR domains is associated with perturbations of the lipid bilayer in the course of ligand-induced receptor activation, considering the receptor together with its lipid environment as a self-consistent signal transduction system.

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.