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Mechanism of receptor assembly via the pleiotropic adipokine Leptin.

Tsirigotaki A, Dansercoer A, Verschueren KHG, Marković I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K
Nat Struct Mol Biol (2023)
Related entries: 7z3p, 7z3q, 7z3r, 8av2, 8avb, 8avd, 8ave, 8avf, 8avo, 8b7q

Cited: 4 times
EuropePMC logo PMID: 36959263

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.

Articles citing this publication (4)

  1. Structural insights into the mechanism of leptin receptor activation. Saxton RA, Caveney NA, Moya-Garzon MD, Householder KD, Rodriguez GE, Burdsall KA, Long JZ, Garcia KC. Nat Commun 14 1797 (2023)
  2. Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons. Mao H, Kim GH, Pan L, Qi L. Nat Commun 15 8435 (2024)
  3. Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling. Caveney NA, Rodriguez GE, Pollmann C, Meyer T, Borowska MT, Wilson SC, Wang N, Xiang X, Householder KD, Tao P, Su LL, Saxton RA, Piehler J, Garcia KC. Mol Cell 84 1995-2005.e7 (2024)
  4. Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. Bloch Y, Felix J, Merceron R, Provost M, Symakani RA, De Backer R, Lambert E, Mehdipour AR, Savvides SN. Nat Struct Mol Biol 31 591-597 (2024)


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