Ligand-Induced Architecture of the Leptin Receptor Signaling Complex

Despite the crucial impact of leptin signaling on metabolism and body weight, little is known about the structure of the liganded leptin receptor (LEP-R) complex. Here, we applied single-particle electron microscopy (EM) to characterize the architecture of the extracellular region of LEP-R alone and in complex with leptin. We show that unliganded LEP-R displays significant flexibility in a hinge region within the cytokine homology region 2 (CHR2) that is connected to rigid membrane-proximal FnIII domains. Leptin binds to CHR2 in order to restrict the flexible hinge and the disposition of the FnIII “legs.” Through a separate interaction, leptin engages the Ig-like domain of a second liganded LEP-R, resulting in the formation of a quaternary signaling complex. We propose that the membrane proximal domain rigidification in the context of a liganded cytokine receptor dimer is a key mechanism for the transactivation of Janus kinases (Jaks) bound at the intracellular receptor region. [Display omitted] ► The extracellular architecture of LEP-R is strikingly similar to gp130 and LIF-R ► Unliganded LEP-R is highly flexible in a hinge region within CHR2 ► Leptin employs epitope I to bind to the CHR2 of LEP-R and rigidify its conformation ► Two binary Leptin/LEP-R complexes engage to form a quaternary signaling complex