Abstract
The leptin.leptin receptor (LR) system shows strong similarities to the long chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) cytokine.cytokine receptor systems. The IL-6 family cytokines interact with their receptors through three different binding sites (I-III). We demonstrated previously that leptin has similar binding sites I-III and mapped the interactions between binding site II and cytokine receptor homology domain II (CRH2) (Peelman, F., Van Beneden, K., Zabeau, L., Iserentant, H., Ulrichts, P., Defeau, D., Verhee, A., Catteeuw, D., Elewaut, D., and Tavernier, J. (2004) J. Biol. Chem. 279, 41038-41046). In this study, we built homology models for the CRH1 and Ig-like domains of the LR. The Ig-like domain shows a large conserved surface patch in the beta-sheet formed by beta-strands 3, 6, and 7. Mutations in this patch almost completely abolished the leptin-induced STAT3-dependent reporter activity. We propose that a conserved cluster of residues Leu370, Ala407, Tyr409, His417, and His418 forms the center of binding site III of the LR. We built a hexameric leptin.LR complex model based on the hexameric IL-6 complex. In this model, a conserved hydrophobic protuberance of Val36, Thr37, Phe41, and Phe43 in the A-B loop of leptin fits perfectly in the CRH2 domain, corresponding to the IL-6 alpha-receptor, and forms the center of binding site I. The 2:4 hexameric leptin.LR complex offers a rational explanation for mutagenesis studies and residue conservation.
Highlights
Hypothalamic neurocircuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure
Homology models were built for the mouse leptin1⁄7leptin receptor (LR) CRH1 domain using the crystal structure of the gp130 cytokine receptor homology (CRH) domain as a template [28]
The positions of these glycosylated residues and the disulfide pattern are in complete agreement with the models. These mass spectrometry data indicate that the Ig-like domain of the LR has a disulfide bridge between Cys350 and Cys410 and a unique extra disulfide bridge between Cys411 and Cys416 that is not found in the Ig-like domains of gp130; the leukemia inhibitory factor (LIF), oncostatin M, or granulocyte colony-stimulating factor (G-CSF) receptor; or the IL-6 ␣-receptor
Summary
Hypothalamic neurocircuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. The membrane-proximal CRH domain (CRH2) was identified as the main high affinity binding site of the LR (10 –12), whereas the other CRH domain (CRH1) seems to be not essential for leptin binding and receptor activation [10, 12]. The Ig-like domain and the two fibronectin type III modules are not prerequisites for high affinity leptin binding [10], they are essential for LR activation [12, 13], but the underlying mechanism has not been fully resolved. Cytokines of the gp130 family typically interact with their receptor complex through three different binding sites (I–III) [14]. G-CSF is believed to form a 2:2 tetrameric complex with its receptor, mediated by binding of site II to the CRH domain of a first receptor and by binding of site III to the Ig-like domains of a second receptor [15]. Hexameric Leptin1⁄7Leptin Receptor Complex whereas residues in binding site III presumably bind to the Ig-like domain of the LR [9, 12]
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