Ligand-induced architecture of the leptin receptor signaling complex

Mol Cell. 2012 Nov 30;48(4):655-61. doi: 10.1016/j.molcel.2012.09.003. Epub 2012 Oct 11.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Leptin / chemistry
  • Leptin / metabolism
  • Leptin / pharmacology*
  • Ligands
  • Microscopy, Electron
  • Models, Molecular
  • Protein Conformation / drug effects
  • Receptors, Leptin / chemistry*
  • Receptors, Leptin / isolation & purification
  • Receptors, Leptin / metabolism*
  • Receptors, Leptin / ultrastructure
  • Signal Transduction / drug effects*

Substances

  • Leptin
  • Ligands
  • Receptors, Leptin