THE LEPTIN HEMATOPOIETIC CYTOKINE FOLD IS STABILIZED BY AN INTRACHAINDISULFIDE BOND

Structure prediction algorithms have tagged leptin as the newest membe r of the haemopoietic cytokine family, a diverse class of secreted hor mone-like factors with pleiotropic effects in immunity and haemopoieti c development. While haemopoietic cytokines typically lack sequence si milarity, they conserve a distinctive three-dimensional fold, a four-a lpha-helix bundle structure that is recognized by the cognate family o f haemopoietic cellular receptors. We have constructed a detailed mole cular model of the human leptin helical fold that places the two cyste ine residues of the leptin chain, Cys(96) and Cys(146), in close spati al proximity to each other. In this report, we present evidence that t hese cysteines are involved in an intrachain disulfide bridge that is critical for the structural integrity and stability of leptin. A lepti n variant that is unable to form the disulfide link shows a reduced bi ological response when administered to leptin-deficient, ob/ob mice.