Mechanism of receptor assembly via the pleiotropic adipokine Leptin

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Tsirigotaki, Alexandra | Dansercoer, Ann | Verschueren, Koen | Marković, Iva | Pollmann, Christoph | Hafer, Maximillian | Felix, Jan | Birck, Catherine | van Putte, Wouter | Catteeuw, Dominiek | Tavernier, Jan | Fernando Bazan, J. | Piehler, Jacob | Savvides, Savvas | Verstraete, Kenneth

Edité par CCSD ; Nature Publishing Group -

International audience. 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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