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A Biologically Active Single Chain Human Chorionic Gonadotropin Analog with Altered Receptor Binding Properties¹

Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602-7229

Address all correspondence and requests for reprints to: Dr. Prema Narayan, Department of Biochemistry and Molecular Biology, Life Sciences Building, Green Street, University of Georgia, Athens, Georgia 30602-7229. E-mail: narayan{at}bchiris.bmb.uga.edu

hCG is a heterodimer consisting of an -subunit common among all members of the glycoprotein hormone family, LH, FSH, and TSH, and a unique ß-subunit responsible for receptor specificity. Biologically active single chain analogs of these hormones have been engineered in which the C-terminus of the ß-subunit was fused to the N-terminus of the -subunit (N-ß--C) either with or without a linker such as the hCGß C-terminal peptide (CTP). This tandem order of subunits was chosen based on studies suggesting that the N-terminal region of hCGß and particularly the C-terminal region of the -subunit are important in receptor binding and activation. Single chain hCG (YhCG1) can, in turn, be fused to the LH receptor to yield a hormone-receptor complex that is biologically active in transfected cells. Herein, we report the construction of a new single chain hCG analog (YhCG3) in which the C-terminus of the -subunit is fused to the N-terminus of hCGß via a CTP (N--CTP-ß-C). Compared with YhCG1, this analog binds receptor with a 25- to 30-fold lower affinity, but, surprisingly, is capable of stimulating intracellular cAMP levels to the same extent. Furthermore, YhCG3 can be covalently linked to its receptor to produce a biologically active complex that results in elevated levels of basal cAMP in transfected cells. These results suggest that free N- and C-termini of hCGß and the -subunit, respectively, are not essential for receptor binding and activation and that YhCG3 is in a more efficacious conformation for receptor activation than YhCG1.

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