Thyrotropin, Follitropin, and Chorionic Gonadotropin Expressed as a Single Multifunctional Unit Reveal Remarkable Permissiveness in Receptor-Ligand Interactions

The glycoprotein hormones [chorionic gonadotropin (CG), FSH, LH, and TSH] are composed of a common α-subunit and a hormone-specific β-subunit. Subunit assembly is vital to the in vivo function of these hormones. However, recent in vitro studies using double domain (β-α) and triple domain (β-β-α) single chains have shown that gonadotropin receptor recognition can accommodate conformationally modified ligands. To investigate the extent of flexibility of ligand-receptor interactions, we constructed a single chain tetramer containing three different β-subunits (TSHβ, FSHβ, and CGβ) and a single α-subunit. This analog was inefficiently secreted from transfected Chinese hamster ovary cells, but surprisingly, the protein exhibited all activities comparable to the corresponding heterodimers. Because the α-subunit presumably cannot form the entire array of heterodimeric contacts with all β-subunits simultaneously in the tetra-domain analog, the data show that the complete quaternary subunit-subunit interactions ar...