Ligand-induced architecture of the leptin receptor signaling complex.
| Autor: | Mancour LV; Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA., Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, Herbstman JF, Chou SZ, Skiniotis G |
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| Jazyk: | angličtina |
| Zdroj: | Molecular cell [Mol Cell] 2012 Nov 30; Vol. 48 (4), pp. 655-61. Date of Electronic Publication: 2012 Oct 11. |
| DOI: | 10.1016/j.molcel.2012.09.003 |
| Abstrakt: | 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. (Copyright © 2012 Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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