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

Department of Molecular Biology and Pharmacology, Washington University School of Medicine (V.G.-C., I.B.), St. Louis, Missouri 63110; and Departments of Pathology and Molecular and Cellular Biology, Baylor College of Medicine (T.R.K.), Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Irving Boime, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110. E-mail: iboime{at}pcg.wustl.edu.

The glycoprotein hormones [chorionic gonadotropin (CG), FSH, LH, and TSH] are composed of a common -subunit and a hormone-specific ß-subunit. Subunit assembly is vital to the in vivo function of these hormones. However, recent in vitro studies using double domain (ß-) and triple domain (ß-ß-) 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 ß-subunits (TSHß, FSHß, and CGß) and a single -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 -subunit presumably cannot form the entire array of heterodimeric contacts with all ß-subunits simultaneously in the tetra-domain analog, the data show that the complete quaternary subunit-subunit interactions are essential for the efficient intracellular trafficking of the glycoprotein hormones, but not for receptor recognition. From an evolutionary perspective, the organization of such a multifunctional analog is consistent with the hypothesis that glycoprotein hormone genes were originally linked in tandem and subsequently evolved as independent genes. Our results also indicate that both gonadal and thyroid stimulatory functions can be combined in a unique analog.

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