LOCALIZATION OF LEPTIN BINDING DOMAIN IN THE LEPTIN RECEPTOR

The leptin receptor is a member of the class I cytokine receptor famil y and is involved in the control of appetite and body weight. The pred icted amino acid sequence of the extracellular region of the cloned le ptin receptor differs from that of many other cytokine receptors in th at it contains two homologous segments representing potential ligand b inding sites. After the analysis of various deletion and substitution mutants of the leptin receptor, we found that the first potential bind ing motif is not required for leptin binding and receptor activation, whereas modification of the second potential binding motif can lead to inactive receptor mutants. Further deletion analysis generated a mini mal binding domain that retains high affinity leptin binding. The lept in binding domain thus has been localized to residues 323-640, which c ontain the second segment of cytokine receptor domain/fibronectin type 3 domain (residues 428-635). Coexpression of the active isoform of le ptin receptor (OB-Rb) with an inactive mutant lacking high affinity le ptin binding site led to suppression of the activity mediated by OB-Rb , suggesting that the leptin receptor may exist as a multimeric comple x in the absence of leptin.