Fusion proteins engineered to characterize glycoprotein hormone-receptor interactions
Schubert, Rebecca Lee
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The family of glycoprotein hormones consists of four heterodimeric hormones: human chorionic gonadotropin, luteinizing hormone, thyroid stimulating hormone, and follicle stimulating hormone. Each hormone consists of a common a subunit and a hormonespecific b subunit, which together bind to the N-terminal extracellular domain of their G protein-coupled receptors, stimulating production of cAMP. Proper activation of these receptors is critical for control of normal reproduction and metabolism. Both hCG and LH bind the LH receptor, whereas TSH and FSH bind their unique receptors, TSHR and FSHR, respectively. Structure-function studies of homologous sequences within this family are hampered by the excessive amounts of hormone necessary to study noncognate or low affinity interactions. By fusing a hormone or part of a hormone to a receptor, weak binding events can be evaluated that would otherwise be undetectable. These methods revealed that hCG can activate the non-cognate receptors, TSHR and FSHR, in addition to its cognate receptor, LHR. The minimum number of residues of hCGb required to exhibit binding and activation activity can also be determined in this system. Low molecular weight hCG hormones, or mini-gonadotropins, retaining just one-third of the b subunit were sufficient to cause weak activation of LHR in the absence of full-length hCG. These studies provide valuable information concerning regions of specificity in hCG and the glycoprotein hormone receptors that are responsible for hormone binding and receptor activation, which will aid in the development of clinically relevant low molecular weight agonists and antagonists for these receptors.
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