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Journal Articles Nature Year : 2023

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Wouter van Putte
  • Function : Author

Abstract

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.

Dates and versions

hal-04148477 , version 1 (03-07-2023)

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Alexandra Tsirigotaki, Ann Dansercoer, Koen Verschueren, Iva Marković, Christoph Pollmann, et al.. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Nature, 2023, 30 (4), pp.551-563. ⟨10.1038/s41594-023-00941-9⟩. ⟨hal-04148477⟩
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