BIOSYNTHESIS OF A BIOLOGICALLY-ACTIVE SINGLE PEPTIDE-CHAIN CONTAININGTHE HUMAN COMMON ALPHA-SUBUNITS AND CHORIONIC-GONADOTROPIN BETA-SUBUNITS IN TANDEM

One of the distinguishing features of the gonadotropin and thyrotropin hormone family is their heterodimeric structure, consisting of a comm on alpha subunit and a hormone-specific beta subunit. Subunit assembly is vital to the function of these hormones: The conformation of the h eterodimer is essential for controlling secretion, hormone-specific po sttranslational modifications, and signal transduction. To address whe ther alpha and beta subunits can be synthesized as one chain and also maintain biological activity, a chimera composed of the human chorioni c gonadotropin (hCG) beta subunit genetically fused to the alpha subun it was constructed. The resulting polypeptide hCG molecule not only wa s efficiently secreted but also displayed an increased biological acti vity in vitro and in vivo. These data show that the alpha and hCG beta subunits encoded as a single chain retain a biologically active confo rmation similar to that seen in the heterodimer. This approach can be used to investigate structure-function relationships of the glycoprote in hormone family that were previously not tractable because of the ab solute dependence on assembly for the biological response. Moreover, o ther bioactive multisubunit ligands can be engineered where the combin ation efficiency and specificity of heterodimers and homodimers are ot herwise difficult to control.