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Independent Activities of FSH and LH Structurally Confined in a Single Polypeptide: Selective Modification of the Relative Potencies of the Hormones

Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Irving Boime, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: iboime{at}pcg.wustl.edu

The human glycoprotein hormones CG, LH, FSH, and TSH are heterodimers composed of a common subunit noncovalently associated with a hormone-specific ß subunit. Recently, it was reported that a covalently fused triple-domain gonadotropin analog containing FSHß, CGß, and subunits was dually active because it bound to both FSH and human CG (hCG)/LH receptors. However, it is not known whether both activities can be uncoupled from each other or whether they change in tandem when modifications are made in the molecule. To address this point, we constructed a triple-domain analog containing FSHß, LHß, and subunits, and variants of this analog differing in the carboxyl-terminal region of LHß. All of the analogs exhibited bifunctional action, i.e. they bound to both LH/hCG and human FSH receptors. FSH binding and signal transduction were similar for all variants and differed less than 2-fold from that of the heterodimer. In contrast, the triple-domain variants manifested distinct individual differences in LH activity. Binding affinity of the longest variant was 30-fold lower than that of the heterodimer. Shortening the length of the LHß carboxyl-terminal region resulted in decreasing affinities between 210- and more than 480-fold. The potency of adenylate cyclase activation for LH/hCG also decreased as the carboxyl length of LHß subunit decreased. Thus, while minimally affecting the FSH activity, truncating the carboxyl end of the LHß subunit in the triple-domain analogs alters the alignment of the LHß- domains, presumably at the junction between the subunits, and perturbs epitopes required for receptor binding. These data imply that the relative potencies of the two gonadotropin components of a triple-domain structure are independent from each other and can be selectively modified. Because there is a strong rationale for FSH/LH combinations for clinical protocols and patients exhibit variations in metabolic responses in the ratio of FSH/LH, the ability to vary the individual activities represents a potential addition to the therapeutic repertoire for treating infertility.

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