Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation.
Fiche publication
Date publication
novembre 2020
Journal
Biochimica et biophysica acta. Biomembranes
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BENNASROUNE Amar
Tous les auteurs :
Kuznetsov AS, Zamaletdinov MF, Bershatsky YV, Urban AS, Bocharova OV, Bennasroune A, Maurice P, Bocharov EV, Efremov RG
Lien Pubmed
Résumé
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 different membrane-mimicking environments 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.
Mots clés
Dimer structure prediction, Dimerization, Free energy of helix-helix association, Insulin receptor, Protein-protein interactions in membrane, Transmembrane domain
Référence
Biochim Biophys Acta Biomembr. 2020 11 1;1862(11):183417