Mechanism of receptor assembly via the pleiotropic adipokine Leptin
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- Alexandra Tsirigotaki (UGent) , Ann Dansercoer (UGent) , Koen Verschueren (UGent) , Iva Marković (UGent) , Christoph Pollmann, Maximillian Hafer, Jan Félix (UGent) , Catherine Birck, Wouter Van Putte, Dominiek Catteeuw (UGent) , Jan Tavernier (UGent) , J. Fernando Bazan, Jacob Piehler, Savvas Savvides (UGent) and Kenneth Verstraete (UGent)
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- Abstract
- Tsirigotaki et al. unveil how adipokine Leptin induces trimerization of the Leptin receptor to form a cytokine-receptor assembly critical to body weight regulation, immunity, fertility and cancer. The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01H7ZB26R7R8CHK1XQ3VJM3907
- MLA
- Tsirigotaki, Alexandra, et al. “Mechanism of Receptor Assembly via the Pleiotropic Adipokine Leptin.” NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 30, no. 4, 2023, pp. 551–63, doi:10.1038/s41594-023-00941-9.
- APA
- Tsirigotaki, A., Dansercoer, A., Verschueren, K., Marković, I., Pollmann, C., Hafer, M., … Verstraete, K. (2023). Mechanism of receptor assembly via the pleiotropic adipokine Leptin. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 30(4), 551–563. https://doi.org/10.1038/s41594-023-00941-9
- Chicago author-date
- Tsirigotaki, Alexandra, Ann Dansercoer, Koen Verschueren, Iva Marković, Christoph Pollmann, Maximillian Hafer, Jan Félix, et al. 2023. “Mechanism of Receptor Assembly via the Pleiotropic Adipokine Leptin.” NATURE STRUCTURAL & MOLECULAR BIOLOGY 30 (4): 551–63. https://doi.org/10.1038/s41594-023-00941-9.
- Chicago author-date (all authors)
- Tsirigotaki, Alexandra, Ann Dansercoer, Koen Verschueren, Iva Marković, Christoph Pollmann, Maximillian Hafer, Jan Félix, Catherine Birck, Wouter Van Putte, Dominiek Catteeuw, Jan Tavernier, J. Fernando Bazan, Jacob Piehler, Savvas Savvides, and Kenneth Verstraete. 2023. “Mechanism of Receptor Assembly via the Pleiotropic Adipokine Leptin.” NATURE STRUCTURAL & MOLECULAR BIOLOGY 30 (4): 551–563. doi:10.1038/s41594-023-00941-9.
- Vancouver
- 1.Tsirigotaki A, Dansercoer A, Verschueren K, Marković I, Pollmann C, Hafer M, et al. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. NATURE STRUCTURAL & MOLECULAR BIOLOGY. 2023;30(4):551–63.
- IEEE
- [1]A. Tsirigotaki et al., “Mechanism of receptor assembly via the pleiotropic adipokine Leptin,” NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 30, no. 4, pp. 551–563, 2023.
@article{01H7ZB26R7R8CHK1XQ3VJM3907, abstract = {{Tsirigotaki et al. unveil how adipokine Leptin induces trimerization of the Leptin receptor to form a cytokine-receptor assembly critical to body weight regulation, immunity, fertility and cancer. The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.}}, author = {{Tsirigotaki, Alexandra and Dansercoer, Ann and Verschueren, Koen and Marković, Iva and Pollmann, Christoph and Hafer, Maximillian and Félix, Jan and Birck, Catherine and Van Putte, Wouter and Catteeuw, Dominiek and Tavernier, Jan and Fernando Bazan, J. and Piehler, Jacob and Savvides, Savvas and Verstraete, Kenneth}}, issn = {{1545-9993}}, journal = {{NATURE STRUCTURAL & MOLECULAR BIOLOGY}}, language = {{eng}}, number = {{4}}, pages = {{551--563}}, title = {{Mechanism of receptor assembly via the pleiotropic adipokine Leptin}}, url = {{http://doi.org/10.1038/s41594-023-00941-9}}, volume = {{30}}, year = {{2023}}, }
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