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|Title:||Fusion proteins of human gonadotropins and gonadotropin-receptor complexes|
|Abstract:||Three glycoprotein hormones comprise the family of gonadotropins in humans, luteinizing hormone (LH), chorionic gonadotropin (CG), and follicle stimulating hormone (FSH), composed of a common α subunit and a hormone-specific β subunit. These heterodimers act via two G protein-coupled receptors, the LH receptor (LHR) and the FSH receptor (FSHR), that are expressed on gonadal cells. The β subunits of LH and CG are sufficiently similar that the two holoproteins bind to and activate a common receptor, LHR. Using protein engineering, several laboratories, including ours, have designed and expressed bioactive fusion proteins of the two subunits of human CG, LH, and FSH. Most of these have been of the form,N- β -α-C, although the reverse configuration, N-α-β-C, has been shown to be active as well. Complementing this approach, bioactive intersubunit disulfide-linked gonadotropins, i .e. α-S-S- β, have also been designed and expressed. Site-directed mutagenesis has been used to prepare a number of altered forms of the single chain and intersubunit disulfide-linked gonadotropins, including single amino acid residue replacements, deletions, elimination of N-linked glycosylation sites, and elimination of disulfides. In many cases it was found, quite surprisingly , that the properties of the mutant fusion and intersubunit disulfide-linked gonadotropins were not predictable from the known characteristics of the same alterations of the individual subunits. Thus, such complexes provide unique reagents for research and eventual clinical utilization. Extending the studies on fusion gonadotropins, our laboratory has designed and expressed yoked or single chain human CG-LHR complexes such as N-α-CG β -LHR-C and N-CG β-α-LHR-C, with the carboxy-terminal peptide of CGβ serving as a linker. These membrane- associated fusion proteins lead to constitutive receptor activation as judged by extraordinarily high levels of cellular basal cAMP in transfected cells. This paper reviews the myriad forms of single chain gonadotropins, single chain gonadotropin- receptor complexes, and intersubunit disulfide-linked gonadotropins that have recently been described.|
|ISSN:||0975-1009 (Online); 0019-5189 (Print)|
|Appears in Collections:||IJEB Vol.40(04) [April 2002]|
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