title: The leptin haemopoietic cytokine fold is stabilized by an intrachain disulfide bond.
abstract: Structure prediction algorithms have tagged leptin as the newest member of the haemopoietic cytokine family, a diverse class of secreted hormone-like factors with pleiotropic effects in immunity and haemopoietic development. While haemopoietic cytokines typically lack sequence similarity, they conserve a distinctive three-dimensional fold, a four-alpha-helix bundle structure that is recognized by the cognate family of haemopoietic cellular receptors. We have constructed a detailed molecular model of the human leptin helical fold that places the two cysteine residues of the leptin chain, Cys96 and Cys146, in close spatial proximity to each other. In this report, we present evidence that these cysteines are involved in an intrachain disulfide bridge that is critical for the structural integrity and stability of leptin. A leptin variant that is unable to form the disulfide link shows a reduced biological response when administered to leptin-deficient, ob/ob mice.
authors.affiliation: Department of Molecular Biology, DNAX Research Institute, Palo Alto, CA 94304-1104, USA.
authors.forename: F L
authors.initials: FL
authors.lastname: Rock
authors.forename: S W
authors.initials: SW
authors.lastname: Altmann
authors.forename: M
authors.initials: M
authors.lastname: van Heek
authors.forename: R A
authors.initials: RA
authors.lastname: Kastelein
authors.forename: J F
authors.initials: JF
authors.lastname: Bazan
mesh_terms: D000465:Algorithms; D000818:Animals; D001066:Appetite / Q000187:drug effects; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D020738:Leptin; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D004220:Disulfides; D020738:Leptin; D011506:Proteins; D011994:Recombinant Proteins; D003545:Cysteine