Abstract
Relaxin-like peptides (RLN/INSL) play diverse roles in reproductive and neuroendocrine processes in placental mammals and are functionally associated with two distinct types of receptors (RXFP) for each respective function. The diversification of RLN/INSL and RXFP gene families in vertebrates was predominantly driven by whole genome duplications (2R and 3R). Teleosts preferentially retained duplicates of genes putatively involved in neuroendocrine regulation, harboring a total of 10-11 receptors and 6 ligand genes, while most mammals have equal numbers of ligands and receptors. To date, the ligand-receptor relationships of teleost Rln/Insl peptides and their receptors have largely remained unexplored. Here, we use selection analyses based on sequence data from 5 teleosts and qPCR expression data from zebrafish to explore possible ligand-receptor pairings in teleosts. We find support for the hypothesis that, with the exception of RLN, which has undergone strong positive selection in mammalian lineages, the ligand and receptor genes shared between mammals and teleosts appear to have similar pairings. On the other hand, the teleost-specific receptors show evidence of subfunctionalization. Overall, this study underscores the complexity of RLN/INSL and RXFP ligand-receptor interactions in teleosts and establishes theoretical background for further experimental work in nonmammals.
Highlights
Relaxin-like peptides are members of the insulin superfamily and, like insulin and insulin-like growth factors (IGF), are small peptides (∼60 amino acids) that share a common twodomain structure (A and B domains) in their mature form [1]
Codons were found to have evidence of positive selection to their position in the mature proteins; we find that (1) the low-density lipoprotein/leucine rich repeat (LDL/leucine-rich repeats (LRR)) region of RXFP1/2-type genes is an important region of diversification among lineages; (2) for the 7 transmembrane (7TM) region shared between the two receptor types, all regions have more selected sites in RXFP3/4- than in RXFP1/2-type genes, except extracellular loop 2 (ECL2), and (3) intracellular loops 1 (ICL1) and 3 (ICL3) have many positively selected sites for RXFP3/4 genes while ICL3 has many amino acids selected for RXFP1/2 type genes (Figure 7)
Earlier studies suggested that teleosts only possessed relaxin 3- and rxfp3-like genes and proposed that RLN and INSL3 were neurohormones that recruited their RXFP1/2type receptors after the divergence of mammals [28], a view that is inconsistent with the data presented here and elsewhere [2, 8, 29, 30]
Summary
Relaxin-like peptides are members of the insulin superfamily and, like insulin and insulin-like growth factors (IGF), are small peptides (∼60 amino acids) that share a common twodomain structure (A and B domains) in their mature form [1]. Relaxin family peptides are different from insulin and IGF: they bind to unrelated receptors and play diverse roles in reproduction and neuroendocrine regulation as opposed to carbohydrate/fat metabolism and growth. RXFP1 and RXFP2 are evolutionarily related to glycoprotein hormone receptors (e.g., luteinizing and follicle-stimulating hormone receptors), containing a large extracellular domain made up of ten leucine-rich repeats (LRR) and a low-density lipoprotein receptor type A (LDLa) module; they are the cognate receptors for the ligands RLN and INSL3 in humans, both of which primarily have reproductive actions [3]. RXFP3 and RXFP4 are classic type I peptide GPCRs with short N-terminal domains; they are evolutionarily related to somatostatin and angiotensin receptors and, in humans, are the cognate receptors for RLN3 and INSL5, both of which are associated with neuroendocrine signaling [3]
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