Gonadotropin Subunits

FSH, LH, and hCG, together with thyroid-stimulating hormone (TSH), comprise the family of glycoprotein hormones. Each hormone is composed of two subunits that are coupled by noncovalent interactions: the common a-subunit of 92 amino acids (aa) and the P-subunit; 110 aa in FSH, 121 aa in LHp, and 145 aa in hCGp (see Fig. 1). The different P-subunits of the glycoprotein hormones are responsible for their functional specificity. hCG is structurally similar to LH, and both hormones have similar actions. Gonadotropins are glycosylated through ^-linked bonds (see Fig. 1), and the carbohydrate content of LH is approx 15%, of FSH is 20%, and of hCG is 30% (1,2). Most conspicuously, the carbohydrate moieties increase the circulatory half-lives of the gonadotropins, which are approx 20 min for LH, approx 2 h for FSH, and 12-24 h for hCG. The long half-life of hCG is primarily explained by the 24-aa C-terminal extension of its P-subunit, in comparison to LHP, which is heavily glycosylated through O-linked glycosylation sites (see Fig. 1). The short half-life of LH is a function of the high proportion of terminal sulphate groups in its carbohydrates; a specific hepatic receptor accelerates the elimination of this type of glycoprotein from the circulation (3).

The common a-subunit gene is located on chromosome 6q12.21, FSHfi is found on chromosome 11p13, and the cluster of LHp/hCGP genes, consisting of one LHP and six hCGP genes and pseudogenes, is located on chromosome 19q13.32 (4,5). The common a-subunit gene consists of four exons, and the p-subunits are composed of three exons. The crystal structures of deglycosylated hCG (6) and FSH (7) are similar and reveal that both subunits contain so-called "cysteine knot structures" that are similar to some remotely related growth factor-type signaling molecules. Each subunit has an elongated shape, with two P-hairpin loops on one side of the central cysteine knot and a long loop on the other side. The noncovalent interaction between the two subunits is stabilized by a segment of the P-subunit that extends like a "seatbelt" around the a-subunit and is "locked" by a disulfide bridge.

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