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000584708 1001_ $$aTsirigotaki, Alexandra$$b0
000584708 245__ $$aMechanism of receptor assembly via the pleiotropic adipokine Leptin
000584708 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2023
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000584708 520__ $$aThe adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.
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000584708 7001_ $$aDansercoer, Ann$$b1
000584708 7001_ $$aVerschueren, Koen H. G.$$b2
000584708 7001_ $$0P:(DE-H253)PIP1090797$$aMarkovic, Iva$$b3
000584708 7001_ $$aPollmann, Christoph$$b4
000584708 7001_ $$aHafer, Maximillian$$b5
000584708 7001_ $$0P:(DE-HGF)0$$aFelix, Jan$$b6
000584708 7001_ $$00000-0003-1624-255X$$aBirck, Catherine$$b7
000584708 7001_ $$aVan Putte, Wouter$$b8
000584708 7001_ $$aCatteeuw, Dominiek$$b9
000584708 7001_ $$00000-0002-7609-6462$$aTavernier, Jan$$b10
000584708 7001_ $$aFernando Bazan, J.$$b11
000584708 7001_ $$00000-0002-2143-2270$$aPiehler, Jacob$$b12
000584708 7001_ $$0P:(DE-H253)PIP1016941$$aSavvides, Savvas$$b13$$eCorresponding author
000584708 7001_ $$0P:(DE-H253)PIP1016901$$aVerstraete, Kenneth$$b14$$eCorresponding author
000584708 773__ $$0PERI:(DE-600)2131437-8$$a10.1038/s41594-023-00941-9$$gVol. 30, no. 4, p. 551 - 563$$n4$$p551 - 563$$tNature structural & molecular biology$$v30$$x1545-9993$$y2023
000584708 8564_ $$uhttps://www.nature.com/articles/s41594-023-00941-9
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000584708 8564_ $$uhttps://bib-pubdb1.desy.de/record/584708/files/Tsirigotaki_etal_accepted_manuscript.pdf.pdf$$yPublished on 2023-03-23. Available in OpenAccess from 2023-09-23.
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