Position of Pro and Ser near Glu 7.32 in the Extracellular Loop 3 of Mammalian and Nonmammalian Gonadotropin-Releasing Hormone (GnRH) Receptors Is a Critical Determinant for Differential Ligand Selectivity for Mammalian GnRH and Chicken GnRH-II

Sungkyunkwan University, Sŏul, Seoul, South Korea
Molecular Endocrinology (Impact Factor: 4.02). 02/2004; 18(1):105-16. DOI: 10.1210/me.2003-0101
Source: PubMed


A Glu/Asp7.32 residue in the extracellular loop 3 of the mammalian GnRH receptor (GnRHR) is known to interact with Arg8 of mammalian GnRH (mGnRH), which may confer preferential ligand selectivity for mGnRH than for chicken GnRH-II (cGnRH-II). However, some nonmammalian GnRHRs also have the Glu/Asp residue at the same position, yet respond better to cGnRH-II than mGnRH. Amino acids flanking Glu/Asp7.32 are differentially arranged such that mammalian and nonmammalian GnRHRs have an S-E/D-P motif and P-X-S/Y motif, respectively. We presumed the position of Ser7.31 or Pro7.33 of rat GnRHR as a potential determinant for ligand selectivity. Either placing Pro before Glu7.32 or placing Ser after Glu7.32 significantly decreased the sensitivity and/or efficacy for mGnRH, but slightly increased that for cGnRH-II in several mutant receptors. Among them, those with a PEV, PES, or SES motif exhibited a marked decrease in sensitivity for mGnRH such that cGnRH-II had a higher potency than mGnRH, showing a reversed preferential ligand selectivity. Chimeric mGnRHs in which positions 5, 7, and/or 8 were replaced by those of cGnRH-II revealed a greater ability to activate these mutant receptors than mGnRH, whereas they were less potent to activate wild-type rat GnRHR than mGnRH. Interestingly, a mutant bullfrog type I receptor with the SEP motif exhibited an increased sensitivity for mGnRH but a decreased sensitivity for cGnRH-II. These results indicate that the position of Pro and Ser near Glu7.32 in the extracellular loop 3 is critical for the differential ligand selectivity between mammalian and nonmammalian GnRHRs.

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    • "Duplicated paralogs of peptides and receptors have undergone sequence modifications during evolution, leading to diversification and specification of ligand-receptor pairs. Specific diversification of peptides, in other words, conservation within orthologs but variation among paralogs could confer selective interaction of a peptide with the cognate receptor, allowing discrimination of paralogous receptors [27], [55], [56], [57]. Consistent with this hypothesis, we observed that the K16M/I17K18 motif in GCRP is conserved amongst vertebrates but shows variation from the corresponding residues in other peptides. "
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    • "Representative sequences of non-mammalian type I GnRH-Rs (mouse and human) and amphibian type I, II, and III GnRH-Rs (bullfrog) were compared with the three identified GnRH receptors in the lamprey (Flanagan et al., 1994, 1999; Zhou et al., 1994, 1995; Arora et al., 1995, 1997; Davidson et al., 1996; Ballesteros et al., 1998; Myburgh et al., 1998; Chung et al., 1999; Fromme et al., 2001; Kitanovic et al., 2001; Millar et al., 2004; Wang et al., 2004; Li et al., 2005; Oh et al., 2005). "
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    • "Thus, amino acid sequence comparison of the peptide and receptor with their orthologs and paralogs, along with mutational mapping approaches, are useful tools helping to determine specific residues in the peptide ligands and receptors that are essential for maintaining selective ligand-receptor interaction. Indeed, ligand binding domains identified in mammalian receptors are highly conserved in orthologous non-mammalian receptors, indicating that there is high evolutionary selection pressure to maintain selectivity for their ligands (Acharjee et al., 2004; Wang et al., 2004; Li et al., 2005). Recently, we reported that evolutionarily conserved amino acid residues in GLP-1 and core domains of the GLP1R confer selective ligand-receptor interaction and receptor activation (Moon et al., 2010, 2012). "
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    Frontiers in Endocrinology 11/2012; 3:141. DOI:10.3389/fendo.2012.00141
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