Journal Article

PUBDB-2023-03196

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Tsirigotaki, A. ; Dansercoer, A. ; Verschueren, K. H. G. ; Markovic, I.Extern*EMBL* ; Pollmann, C. ; Hafer, M. ; Felix, J. ; Birck, C. ; Van Putte, W. ; Catteeuw, D. ; Tavernier, J. ; Fernando Bazan, J. ; Piehler, J. ; Savvides, S. (Corresponding author)Extern*EMBL* ; Verstraete, K. (Corresponding author)Extern*EMBL*

2023
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41594-023-00941-9  doi:10.3204/PUBDB-2023-03196

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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2023

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Database coverage:
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