Mechanism of Receptor Assembly Via the Pleiotropic Adipokine Leptin

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2023 Mar 24

PMID 36959263

Authors

Alexandra Tsirigotaki

Ann Dansercoer

Koen H G Verschueren

Iva Markovic

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

Affiliations

Soon will be listed here.

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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