title: A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist.
abstract: Cytokine hormones have a short plasma half-life and require frequent administration. For example, growth hormone replacement involves daily injections. In common with other cytokines, the extracellular domain of the growth hormone receptor circulates as a binding protein, which naturally prolongs the biological half-life of growth hormone. Here we have studied the biological actions of a ligand-receptor fusion of growth hormone and the extracellular domain of its receptor. The genetically engineered ligand-receptor fusion protein was purified from mammalian cell culture. In rats, the ligand-receptor fusion had a 300-times reduced clearance as compared to native growth hormone, and a single injection promoted growth for 10 d, far exceeding the growth seen after administration of native growth hormone. The ligand-receptor fusion forms a reciprocal, head-to-tail dimer that provides a reservoir of inactive hormone similar to the natural reservoir of growth hormone and its binding protein. In conclusion, a ligand-receptor fusion of cytokine to its extracellular receptor generates a potent, long-acting agonist with exceptionally slow absorption and elimination. This approach could be easily applied to other cytokines.
authors.affiliation: School of Medicine and Biomedical Sciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Wilkinson
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Artymiuk
authors.forename: Marc
authors.initials: M
authors.lastname: Teillot
authors.forename: Chantal
authors.initials: C
authors.lastname: Soulard
authors.forename: Caroline
authors.initials: C
authors.lastname: Touvay
authors.forename: Sarbendra L
authors.initials: SL
authors.lastname: Pradhananga
authors.forename: Sue
authors.initials: S
authors.lastname: Justice
authors.forename: Zida
authors.initials: Z
authors.lastname: Wu
authors.forename: Kin C
authors.initials: KC
authors.lastname: Leung
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Strasburger
authors.forename: Jon R
authors.initials: JR
authors.lastname: Sayers
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
mesh_terms: D000818:Animals; D019281:Dimerization; D013006:Growth Hormone / Q000737:chemistry / Q000502:physiology; D019382:Human Growth Hormone / Q000737:chemistry*; D006801:Humans; D007016:Hypophysectomy; D008024:Ligands; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D011986:Receptors, Somatotropin / Q000819:agonists / Q000737:chemistry* / Q000502:physiology
chemical_list: D008024:Ligands; D050505:Mutant Proteins; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D013006:Growth Hormone