Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Autor: Alexandra Tsirigotaki, Ann Dansercoer, Koen H.G. Verschueren, Iva Marković, Christoph Pollmann, Maximillian Hafer, Jan Felix, Catherine Birck, Wouter Van Putte, Dominiek Catteeuw, Jan Tavernier, J. Fernando Bazan, Jacob Piehler, Savvas N. Savvides, Kenneth Verstraete
Rok vydání: 2023
Předmět:
Zdroj: Nature Structural & Molecular Biology. 30:551-563
ISSN: 1545-9985
1545-9993
DOI: 10.1038/s41594-023-00941-9
Popis: The adipokine Leptin activates its type I cytokine 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. Here, we show that Leptin:LEP-R assemblies adopt an unprecedented structure within the type I cytokine receptor family featuring 3:3 stoichiometry. We validate Leptin-induced trimerization of LEP-R in the plasma membrane of living cells via multicolor single molecule microscopy. In mediating such assemblies Leptin undergoes drastic restructuring that activates its site III for binding to the Ig-domain of an adjacent LEP-R molecule in the complex. These interactions are abolished by pathological mutations linked to obesity. Collectively, our study uncovers an evolutionarily conserved Leptin:LEP-R assembly as a new mechanistic blueprint for Leptin-mediated signaling in physiology and disease, including insights into how the lowly abundant signaling-competent isoforms of LEP-R can productively participate in signaling.
Databáze: OpenAIRE
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