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Translational Fusion of Two ß-Subunits of Human Chorionic Gonadotropin Results in Production of a Novel Antagonist of the Hormone

Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India

Address all correspondence and requests for reprints to: Professor Rajan R. Dighe, Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India. E-mail: rdighe{at}mrdg.iisc.ernet.in.

The strategy of translationally fusing the - and ß-subunits of human chorionic gonadotropin (hCG) into a single-chain molecule has been used to produce novel analogs of hCG. Previously we reported expression of a biologically active single-chain analog hCGß expressed using Pichia expression system. Using the same expression system, another analog, in which the -subunit was replaced with the second ß-subunit, was expressed (hCGßß) and purified. hCGßß could bind to LH receptor with an affinity three times lower than that of hCG but failed to elicit any response. However, it could inhibit response to the hormone in vitro in a dose-dependent manner. Furthermore, it inhibited response to hCG in vivo indicating the antagonistic nature of the analog. However, it was unable to inhibit human FSH binding or response to human FSH, indicating the specificity of the effect. Characterization of hCGß and hCGßß using immunological tools showed alterations in the conformation of some of the epitopes, whereas others were unaltered. Unlike hCG, hCGßß interacts with two LH receptor molecules. These studies demonstrate that the presence of the second ß-subunit in the single-chain molecule generated a structure that can be recognized by the receptor. However, due to the absence of -subunit, the molecule is unable to elicit response. The strategy of fusing two ß-subunits of glycoprotein hormones can be used to produce antagonists of these hormones.

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