Human choriogonadotropin binds to a lutropin receptor with essentially no N-terminal extension and stimulates cAMP synthesis.
The lutropin (LH) receptor, which belongs to the family of G-protein coupled receptors, consists of an extracellular hydrophilic N-terminal extension of 341 amino acids and a membrane-embedded C-terminal region of 333 amino acids. This C-terminal region comprises a short N terminus, seven transmembrane domains, three cytoplasmic loops, three exoplasmic loops, and a C terminus. Recently, it was reported that the N-terminal extension of the LH receptor alone or a naturally occurring variant LH receptor similar to the N-terminal extension is capable of binding the hormone with an affinity slightly higher than that of the native receptor. This finding raises a question as to whether the N-terminal extension represents the entire hormone binding site and, if so, how is hormone binding transduced to the activation of a G-protein? In an attempt to answer this important question, we have prepared truncated receptors containing an N-terminal extension as short as 10 amino acids. Surprisingly, the truncated receptors were not only capable of binding the hormone, albeit with low affinities, but also capable of stimulating cAMP synthesis. These results suggest a possibility that the hormone, at least in part, interacts with the membrane-embedded C-terminal region and modulates it to activate adenylate cyclase. The low hormone binding affinities of the truncated receptors taken together with high affinity hormone binding to the N-terminal extension of the LH receptor indicate the existence of two or more contact points between the receptor and the hormone.
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Department of Molecular Biology, University of Wyoming, Laramie 82071-3944.
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D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000378:metabolism* / Q000494:pharmacology; D002872:Chromosome Deletion; D003001:Cloning, Molecular; D003338:Corpus Luteum / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D005260:Female; D007700:Kinetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011974:Receptors, LH / Q000235:genetics* / Q000378:metabolism; D015183:Restriction Mapping; D014162:Transfection
D006063:Chorionic Gonadotropin; D012333:RNA, Messenger; D011974:Receptors, LH; D000242:Cyclic AMP