Co-evolution of ligand-receptor pairs

Abstract

Specific receptors for lutropin (luteinizing hormone; LH) and follitropin (follicle-stimulating hormone; FSH) mediate the actions of human chorionic gonadotropin (hCG) and FSH5 on the gonads. Here we report that short independent sequences of the beta-subunit enable hCG to distinguish between the receptors for FSH and LH. Residues between the 11th and 12th cysteines restrict FSH receptor binding; residues between the 10th and 11th cysteines and, to a much lesser extent, residues carboxy-terminal to the 12th cysteine also affect LH receptor binding. CF101-109, an hCG analogue containing hFSH beta residues between the 11th and 12th cysteines, had high affinity for both LH and FSH receptors. Modifications to CF101-109 that reduce binding to either LH or FSH receptors yield gonadotropin analogues having differing ratios of LH:FSH activity. Ligand-binding specificity of the LH receptor is determined by residues encoded by parts of exons 2-4 and 7-9 which prevent hFSH binding but have little effect on hCG binding. FSH receptor specificity is controlled primarily by residues encoded by exons 5 and 6 that prevent hCG binding but have little effect on hFSH binding. These determinants can be interchanged to create receptor analogues that bind hCG and hFSH. Our observations support a model in which distinct negative determinants restrict ligand-receptor interaction. This explains coevolution of binding specificity in families of homologous ligands and their receptors. Natural or designed manipulation of these determinants leads to the 'evolution' of new, specific protein-protein interactions.

The evolution of the ligand/receptor couple: A long road from comparative endocrinology to comparative genomics

“…In such cases, it is believed, and it has been demonstrated in several specific cases, that the genes encoding the ligand and the receptors are undergoing parallel evolution. One of the first examples of such coevolution is the one of the receptors for LH and FSH, which suggests that indeed the specificity of each ligand / receptor pair is maintained in divergent species (Moyle et al, 1994). More recently the case of prolactin receptors in mammals showed how episodes of adaptative evolution have modified the genes encoding the receptor and the ligand (Li et al, 2005, and references therein).…”

CARACTERIZACIÓN BIOLÓGICA DE LAS GONADOTROFINAS DE LUBINA (Dicentrarchus labrax) Y DESARROLLO DE HERRAMIENTAS BIOTECNOLÓGICAS E INMUNOLÓGICAS PARA SU ESTUDIO

“…In mammals, the specificity barriers between each gonadotropin-receptor couple are such that no cross-signaling occurs under physiological conditions in which hormone concentrations are low (Braun et al, 1991;Moyle et al, 1994). In contrast, there is evidence indicating that the specificity of the piscine gonadotropin receptors is less obvious .…”

“…parece que también esta implicada en la especificidad de unión al receptor y transducción de la señal (Moyle et al, 1994).…”

“…Los GTHRs de mamíferos son altamente específicos con sus ligandos, mostrando menos de 0,1% de actividad cruzada (Braun et al, 1991;Moyle et al, 1994), de manera que la actividad de cada GTH está dirigida solo a aquellas células que expresan su receptor. Sin embargo, en peces teleósteos la especificidad de los GTHRs parece ser menos evidente .…”

“…108). En mamíferos, las barreras de especificidad entre cada pareja receptor-gonadotrofina están bien definidas y son tales que bajo condiciones fisiológicas no hay señalización cruzada (Braun et al, 1991;Moyle et al, 1994). Por el contrario, en peces hay evidencias que indican que la especificidad entre las GTHs y sus receptores es menos obvia .…”