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

Autor: Kuznetsov AS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; National Research University Higher School of Economics, Myasnitskaya ul. 20, Moscow 101000, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation., Zamaletdinov MF; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; Lomonosov Moscow State University, Leninskiye Gory, 1, Moscow 119991, Russian Federation., Bershatsky YV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation., Urban AS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation., Bocharova OV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation., Bennasroune A; UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France., Maurice P; UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France., Bocharov EV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation., Efremov RG; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences RAS, str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation; National Research University Higher School of Economics, Myasnitskaya ul. 20, Moscow 101000, Russian Federation; Moscow Institute of Physics and Technology, Institutsky per., 9, Dolgoprudnyi 141700, Russian Federation. Electronic address: efremov@nmr.ru.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Biomembranes [Biochim Biophys Acta Biomembr] 2020 Nov 01; Vol. 1862 (11), pp. 183417. Date of Electronic Publication: 2020 Jul 23.
DOI: 10.1016/j.bbamem.2020.183417
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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