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First published online May 28, 2005
doi: 10.1242/10.1242/jcs.02386

Journal of Cell Science 118, 2519-2527 (2005)
Published by The Company of Biologists 2005
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Research Article

Mapping of the interface between leptin and the leptin receptor CRH2 domain

Hannes Iserentant*, Frank Peelman*, Delphine Defeau, Joël Vandekerckhove, Lennart Zabeau and Jan Tavernier{ddagger}

Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research (VIB09), Ghent University, Faculty of Medicine and Health Sciences, Baertsoenkaai 3, 9000 Ghent, Belgium

{ddagger} Author for correspondence (e-mail: jan.tavernier{at}ugent.be)

Accepted 16 March 2005

Despite the impact of the leptin system on body weight and other physiologic processes, little is known about the binding of leptin to its receptor. The extracellular domain of the leptin receptor consists of two cytokine receptor homology (CRH) domains separated by an immunoglobulin-like domain, and followed by two juxtamembrane fibronectin type III modules. The CRH2 domain functions as a high-affinity binding site for leptin, and we previously demonstrated interaction with helices A and C of leptin. In this work, we constructed a homology model for the leptin/CRH2 complex and performed a detailed mutation analysis of the CRH2/leptin interface. Using both cell-based and in vitro binding assays using the isolated CRH2 domain, we show the critical role of hydrophobic interactions between Leu 13 and Leu 86 of leptin and Leu 504 in CRH2 in leptin binding and signalling. This binding pattern closely resembles the interaction of other four-helix bundle long chain cytokines with the CRH domain of their cognate receptors.

Key words: Cytokines, Leptin, Leptin receptor, Mutagenesis, Molecular modelling




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F. Peelman, H. Iserentant, A.-S. De Smet, J. Vandekerckhove, L. Zabeau, and J. Tavernier
Mapping of Binding Site III in the Leptin Receptor and Modeling of a Hexameric Leptin{middle dot}Leptin Receptor Complex
J. Biol. Chem., June 2, 2006; 281(22): 15496 - 15504.
[Abstract] [Full Text] [PDF]


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