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J. Biol. Chem., Vol. 268, Issue 18, 13034-13042, 06, 1993
J Yoo, H Zeng, I Ji, WJ Murdoch and TH Ji
Human choriogonadotropin (hCG) and follitropin (FSH) belong to the
glycoprotein hormone family. These hormones are heterodimers and composed
of a common alpha subunit and a distinct beta subunit which confers
receptor-binding specificities. In addition to this structural similarity,
they share a similar signal pathway involving G protein, adenylyl-cyclase
and induction of cAMP synthesis. Therefore, a presumptive relationship of
these common structure and function has been the subject of extensive past
investigations, but a definitive clue has been elusive. As a step to
address this important issue, a series of recombinant mutants of hCG and
human FSH were generated in which the COOH-terminal amino acids of the
alpha subunit were successively removed or substituted. Furthermore, a set
of peptides were synthesized with sequences corresponding to different
regions of the alpha subunit. Deletion of the alpha COOH-terminal Ser92 had
no effect on receptor-binding or cAMP induction by FSH and hCG. Truncation
of alpha Lys91-Ser92 or alpha His90-Lys91-Ser92 abolished the ability of
both hormones to induce cAMP synthesis. It significantly reduced receptor
binding of FSH but not hCG. The different functions of the alpha
COOH-terminal region are further noticed with a peptide corresponding to
the last 10 amino acids of alpha. It failed to bind to the FSH receptor but
was capable of binding to the LH/CG receptor and stimulating cAMP
synthesis. These results are the first conclusive evidence that alpha
His90-Lys91 play an essential role in cAMP induction of both hormones. In
contrast to this common role, they are necessary for FSH binding to the FSH
receptor but not for hCG binding to the LH/CG receptor. The hCG alpha
COOH-terminal region makes direct contact with the LH/CG receptor, and this
low affinity contact is necessary and sufficient to activate the receptor
for signal generation. This conclusion is supported by the study using
mutant hCGs in which either alpha His90 or Lys91 was substituted.
COOH-terminal amino acids of the alpha subunit play common and different roles in human choriogonadotropin and follitropin
Department of Molecular Biology, University of Wyoming, Laramie 82071- 3944.
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