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Volume 271, Number 49, Issue of December 6, 1996 pp. 31638-31642
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Protein Engineering of a Novel Constitutively Active Hormone-Receptor Complex

(Received for publication, September 4, 1996, and in revised form, October 9, 1996)

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

Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone consisting of an  and a  subunit that stimulates intracellular levels of cAMP via a G protein-coupled receptor. Herein we report the engineering and characterization of a novel molecule in which the receptor and its heterodimeric ligand were covalently linked in a single polypeptide chain. The hormone-receptor complex was expressed in cells transfected with this construct, but the cells were unable to bind significant amounts of exogenous hCG. However, cleavage of the hormone with a site-specific protease rendered the receptor accessible to exogenously added hormone. Cells transfected with the hCG-receptor construct contained elevated basal levels of cAMP; moreover, addition of hormone had no significant effect. These results are consistent with a strong and stable interaction between the single-chain hormone and its covalently linked receptor that results in a constitutively active complex.

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