Lys91 and His90 of the alpha-subunit are crucial for receptor binding and hormone action of follicle-stimulating hormone (FSH) and play hormone-specific roles in FSH and human chorionic gonadotropin.
Glycoprotein hormones, FSH, LH, CG, and TSH, consist of a common alpha-subunit and a hormone-specific beta-subunit. Both subunits are thought to interact with the hormone receptors. Although several C-terminal residues of hCG alpha are known to contact the LH/CG receptor, little is known about the roles of individual C-terminal residues of FSH alpha. In this report, substitutions of various amino acids for the penultimate Lys91 and the upstream His90 of the alpha-subunit demonstrate that these two residues of FSH alpha are important for high affinity receptor binding and hormone action to induce cAMP production. In contrast, the same residues of hCG alpha are more important for cAMP induction than for high affinity receptor binding. Some substitutions significantly improved receptor binding of FSH and hCG, whereas others were detrimental. Some had the same effect on both hormones, and others impacted differently. Particularly, the substitution of Val for alpha Lys91 resulted in an improved receptor binding of and a loss of cAMP induction by FSH and hCG. On the other hand, the substitution of Arg or Pro for alpha His90 abolished receptor binding of FSH, but not of hCG. These results allowed us to generate an antagonist to FSH. Our results indicate that alpha His90 and alpha Lys91 play roles in receptor binding and cAMP induction of FSH and hCG in strikingly different ways. They will be useful to elucidate the underlying mechanisms for the interaction of FSH and hCG with their complementary receptors as well as for receptor activation.
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Department of Molecular Biology, University of Wyoming, Laramie 82071-3944, USA.
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D000818:Animals; D016466:CHO Cells; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D015292:Glycoprotein Hormones, alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006639:Histidine; D008239:Lysine; D016297:Mutagenesis, Site-Directed; D011962:Receptors, FSH / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D006063:Chorionic Gonadotropin; D015292:Glycoprotein Hormones, alpha Subunit; D011962:Receptors, FSH; D011994:Recombinant Proteins; D006639:Histidine; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D008239:Lysine