Structure of tetrameric forms of the serotonin-gated 5-HT3 A receptor ion channel.

Autor:	Introini B; Max Planck Institute of Biophysics, Frankfurt am Main, Germany.; Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt am Main, Frankfurt on Main, Germany., Cui W; The Research Center for Computer-aided Drug Discovery, Institute of Biomedicine and Biotechnology, The Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Chu X; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), In Situ Structural Biology, Robert-Rössle-Str. 10, 13125, Berlin, Germany., Zhang Y; Max Planck Institute of Biophysics, Frankfurt am Main, Germany.; Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt am Main, Frankfurt on Main, Germany., Alves AC; Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Eckhardt-Strelau L; Max Planck Institute of Biophysics, Frankfurt am Main, Germany., Golusik S; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), In Situ Structural Biology, Robert-Rössle-Str. 10, 13125, Berlin, Germany., Tol M; Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Vogel H; The Research Center for Computer-aided Drug Discovery, Institute of Biomedicine and Biotechnology, The Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. horst.vogel@epfl.ch.; Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. horst.vogel@epfl.ch.; Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology (SUAT), Shenzhen, China. horst.vogel@epfl.ch., Yuan S; The Research Center for Computer-aided Drug Discovery, Institute of Biomedicine and Biotechnology, The Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. shuguang.yuan@cadd2drug.org.; AlphaMol Science Ltd, Shenzhen, 518055, China. shuguang.yuan@cadd2drug.org., Kudryashev M; Max Planck Institute of Biophysics, Frankfurt am Main, Germany. mikhail.kudryashev@mdc-berlin.de.; Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt am Main, Frankfurt on Main, Germany. mikhail.kudryashev@mdc-berlin.de.; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), In Situ Structural Biology, Robert-Rössle-Str. 10, 13125, Berlin, Germany. mikhail.kudryashev@mdc-berlin.de.; Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin, Berlin, Germany. mikhail.kudryashev@mdc-berlin.de.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Oct; Vol. 43 (20), pp. 4451-4471. Date of Electronic Publication: 2024 Sep 04.
DOI:	10.1038/s44318-024-00191-5
Abstrakt:	Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography. The tetrameric structures have near-symmetric transmembrane domains, and asymmetric extracellular domains, and can bind serotonin molecules. Computer simulations, based on our cryo-EM structures, were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors. (© 2024. The Author(s).)
Databáze:	MEDLINE
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