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

Iserentant, Hannes; Peelman, Frank; Defeau, Delphine; Vandekerckhove, Joël; Zabeau, Lennart; Tavernier, Jan

doi:10.1242/jcs.02386

Cited by 66 publications

(72 citation statements)

References 27 publications

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“…It is also possible that the 223R LepR does not dimerize as efficiently as WT LepR and that this reduces basal activation in the absence of ligand. These possibilities warrant further investigation, as previous studies have shown that the domain of LepR containing the Q223R polymorphism is dispensable for leptin binding (35,36,48). Thus, while we have shown that the biological impact of the Q223R polymorphism on amebiasis is likely via reduced levels of STAT3 transcription, the mechanism by which this occurs remains unknown.…”

Section: Discussionmentioning

confidence: 73%

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Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

et al. 2012

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ABSTRACTThe adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed anin vitromodel of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin receptor conferred resistance in susceptible cells, and leptin stimulation enhanced protection. A series of leptin receptor signaling mutants showed that resistance to amebic cytotoxicity was dependent on activation of STAT3 but not the Src homology-2 domain-containing tyrosine phosphatase (SHP-2) or STAT5. A common polymorphism in the leptin receptor (Q223R) that increases susceptibility to amebiasis in humans and mice was found to increase susceptibility to amebic cytotoxicity in single cells. The Q223R polymorphism also decreased leptin-dependent STAT3 activation by 21% relative to that of the wild-type (WT) receptor (P= 0.035), consistent with a central role of STAT3 signaling in protection. A subset of genes uniquely regulated by STAT3 in response to leptin was identified. Most notable were the TRIB1 and suppressor of cytokine signaling 3 (SOCS3) genes, which have opposing roles in the regulation of apoptosis. Overall apoptotic genes were highly enriched in this gene set (P< 1E−05), supporting the hypothesis that leptin regulation of host apoptotic genes via STAT3 is responsible for protection. This is the first demonstration of a mammalian signaling pathway that restricts amebic pathogenesis and represents an important advance in our mechanistic understanding of how leptin links nutrition and susceptibility to infection.

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Section: Discussionmentioning

confidence: 73%

“…The plasmids mLEPRb/pCDNA3 (47), mLEPRbR223/pCDNA3 (35), and LEPRbDelta65/pCDNA3 (47) were obtained from Martin Myers and have been described previously as referenced. pCDNA3 was used as a vector control.…”

Section: Methodsmentioning

confidence: 99%

Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

et al. 2012

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“…5) are structurally similar and face the same orientation, and they are most likely involved in interacting with CHR2. Mutations of those residues, such as D9S, T12Q, K15S, T16N, R20N, Q75S, N82S, D85S and L86A, L86S, L86N, and L86Q, significantly lowered the affinity of leptin for CHR2 and affected both binding and leptin receptor signaling (4,5). To date, no report regarding the putative role of Asp-23 has been published; nevertheless, our data (see Table 3) strongly indicate that replacement of Asp-23 by any non-negatively charged amino acid is sufficient to increase affinity for hLBD (CHR2) and subsequent biological activity.…”

Section: Discussionmentioning

confidence: 99%

Development and Characterization of High Affinity Leptins and Leptin Antagonists

Shpilman

Niv-Spector

Katz

et al. 2011

Journal of Biological Chemistry

124

117

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Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/ D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/ F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.Leptin, a 16-kDa protein, is a central regulator of body weight (1), as well as a pleiotropic hormone whose involvement in many physiological processes has been well established (2). The three-dimensional structure of leptin was elucidated shortly after its discovery (3), but so far no structural information on its complex with leptin receptor has been published. Although several theoretical models of such a complex have been proposed (4 -6), lack of a valid crystallographic structure hampers reliable structural interpretation of any new leptin mutations. In the last decade, leptin has also been documented as a major regulator of the innate and adaptive immune response and a modulator of the onset and progression of autoimmunity in several animal models of disease (7), including rheumatoid arthritis, experimental autoimmune encephalomyelitis (4), and immune-mediated colitis (8). Work published from our and others' laboratories has also shown that leptin enhances thioacetamide-induced liver fibrosis (9) and liver inflammation in several mouse models (10). In addition, leptin acts as a mitogenic agent in many tissues and is suggested to promote cancer cell growth. In fact...

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“…Different theories about the origin of obesity have been proposed, one of these theories is the phenomenon called Leptin resistance and it is related to the pathologically increase of Leptin (LEP) levels due to saturation of the transport of this hormone in obese persons (Banks et al, 1996;Bjorbaek et al, 1999;Bahrenberg et al, 2002;Scarpace et al, 2005;Myers et al, 2010;Fuentes et al, 2010). The interaction of Leptin with its receptor has been investigated through amino acid replacements and deletion experiments demonstrating that some regions affect the LEP-LEPR interaction (Bahrenberg et al, 2002;Devos et al, 1997;Fong et al, 1998;Iserentant et al, 2005;Peelman et al, 2004;. Therefore, Leptin resistance could be related to mutations and SNPs of Leptin receptor gene (lepr) and recently associated to increase risk of insulin resistance and metabolic syndrome (Bjorbaek et al, 1999;Bjorbaek et al, 1997;Enriori et al, 2006;Phillips et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Structural Consequences of the Polymorphism Q223r in the Human Leptin Receptor: A Molecular Dynamics Study

Carrillo-VÃ¡zquez¹

2013

American Journal of Agricultural and Biological Sciences

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Leptin Receptor (LEPR) is a component of a signaling pathway related to appetite and energy expenditure. Single Nucleotide Polymorphisms (SNP) of Leptin receptor gene (lepr) have been proposed as possible modulator of adipose tissue and body weight. The main phenomenological consequence reported of these SNPs is the modulation of the LEP-LEPR interaction promoting the weight gain. Particularly, Q223R polymorphism has been associated with human obesity in some populations. In this work, we analyze the structural effects of Q223R substitution in a model of the extracellular region of LEPR comparing the stability between LEPR-Q and its Q223R variant (rs1137101) by Molecular Dynamics (MD) simulations. These results showed different behavior between both molecules after one nanosecond (ns) of simulation and significant differences in the secondary structure content were evidenced.

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

Cited by 66 publications

References 27 publications

Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

Development and Characterization of High Affinity Leptins and Leptin Antagonists

Structural Consequences of the Polymorphism Q223r in the Human Leptin Receptor: A Molecular Dynamics Study

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