Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Tsirigotaki, A.; Dansercoer, A.; Verschueren, K. H. G.; Markovic, I.; Pollmann, C.; Hafer, M.; Felix, J.; Birck, C.; Van Putte, W.; Catteeuw, D.; Tavernier, J.; Bazan, F. J.; Piehler, J.; Savvides, S. N.; Verstraete, K.

doi:10.1101/2022.12.01.518327

bioRxiv · 10.1101/2022.12.01.518327

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Tsirigotaki, A.·Dansercoer, A.·Verschueren, K. H. G.·Markovic, I.·Pollmann, C.·Hafer, M.·Felix, J.·Birck, C.·Van Putte, W.·Catteeuw, D.·Tavernier, J.·Bazan, F. J.·Piehler, J.·Savvides, S. N.·Verstraete, K.

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Abstract

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.

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Tsirigotaki, A., Dansercoer, A., Verschueren, K. H. G., Markovic, I., Pollmann, C., Hafer, M., Felix, J., Birck, C., Van Putte, W., Catteeuw, D., Tavernier, J., Bazan, F. J., Piehler, J., Savvides, S. N., Verstraete, K.. 2022-12-01. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. https://doi.org/10.1101/2022.12.01.518327

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