8AVF

Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric isoleucine GCN4 zipper (closed 3:3 model)

Summary for 8AVF

• Entry DOI: 10.2210/pdb8avf/pdb
• Related: 7z3q 7z3r
• EMDB information: 15681
• Descriptor: Leptin, Leptin receptor (2 entities in total)
• Functional Keywords: leptin, lep-r, obesity, metabolism, energy balance, cytokine
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 352281.37

Authors

Verstraete, K.,Savvides, S.N.,Verschueren, K.G.,Tsirigotaki, A. (deposition date: 2022-08-26, release date: 2023-04-05, Last modification date: 2023-04-26)

Primary citation

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.,Fernando Bazan, J.,Piehler, J.,Savvides, S.N.,Verstraete, K.
Mechanism of receptor assembly via the pleiotropic adipokine Leptin.
Nat.Struct.Mol.Biol., 30:551-563, 2023

PubMed 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.

PubMed: 36959263
DOI: 10.1038/s41594-023-00941-9

Experimental method

ELECTRON MICROSCOPY (6.45 Å)