The Conformational Equilibrium of the Neuropeptide Y2 Receptor in Bilayer Membranes
| Autor: | Clemens Glaubitz, Frank Bernhard, Cindy Montag, Johanna Becker-Baldus, Sergey A. Vishnivetskiy, Vsevolod V. Gurevich, Ulrike Krug, Peter Schmidt, Marcel Gauglitz, Daniel Huster, Anette Kaiser, Annette G. Beck-Sickinger, Anika Gloge |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular Molecular Conformation receptors Receptors | Hot Paper 010402 general chemistry 01 natural sciences Catalysis NMR spectroscopy Extracellular Arrestin Humans Research Articles Molecular switch arrestin 010405 organic chemistry Chemistry Bilayer General Chemistry Nuclear magnetic resonance spectroscopy Carbon-13 NMR structural dynamics Neuropeptide Y receptor Receptors Neuropeptide Y molecular switch 0104 chemical sciences Membrane Biophysics 500 Naturwissenschaften und Mathematik::540 Chemie::540 Chemie und zugeordnete Wissenschaften Research Article |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202006075 |
| Popis: | Dynamic structural transitions within the seven‐transmembrane bundle represent the mechanism by which G‐protein‐coupled receptors convert an extracellular chemical signal into an intracellular biological function. Here, the conformational dynamics of the neuropeptide Y receptor type 2 (Y2R) during activation was investigated. The apo, full agonist‐, and arrestin‐bound states of Y2R were prepared by cell‐free expression, functional refolding, and reconstitution into lipid membranes. To study conformational transitions between these states, all six tryptophans of Y2R were 13C‐labeled. NMR‐signal assignment was achieved by dynamic‐nuclear‐polarization enhancement and the individual functional states of the receptor were characterized by monitoring 13C NMR chemical shifts. Activation of Y2R is mediated by molecular switches involving the toggle switch residue Trp2816.48 of the highly conserved SWLP motif and Trp3277.55 adjacent to the NPxxY motif. Furthermore, a conformationally preserved “cysteine lock”‐Trp11623.50 was identified. Structural transitions of crucial molecular switches of the activation of the human neuropeptide Y receptor type 2 are reported from the 13C‐tryptophan labeled molecule by solid‐state NMR spectroscopy in lipid membranes. The molecule shows high structural dynamics in the apo and agonist‐bound states, which is reduced by arrestin binding. |
| Databáze: | OpenAIRE |
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