Conservation of pregnancy-specific glycoprotein (PSG) N domains following independent expansions of the gene families in rodents and primates

Department of Biochemistry, Biosciences Institute, University College Cork, College Road, Cork, Ireland.
BMC Evolutionary Biology (Impact Factor: 3.37). 02/2005; 5(1):39. DOI: 10.1186/1471-2148-5-39
Source: PubMed


Rodent and primate pregnancy-specific glycoprotein (PSG) gene families have expanded independently from a common ancestor and are expressed virtually exclusively in placental trophoblasts. However, within each species, it is unknown whether multiple paralogs have been selected for diversification of function, or for increased dosage of monofunctional PSG. We analysed the evolution of the mouse PSG sequences, and compared them to rat, human and baboon PSGs to attempt to understand the evolution of this complex gene family.
Phylogenetic tree analyses indicate that the primate N domains and the rodent N1 domains exhibit a higher degree of conservation than that observed in a comparison of the mouse N1 and N2 domains, or mouse N1 and N3 domains. Compared to human and baboon PSG N domain exons, mouse and rat PSG N domain exons have undergone less sequence homogenisation. The high non-synonymous substitution rates observed in the CFG face of the mouse N1 domain, within a context of overall conservation, suggests divergence of function of mouse PSGs. The rat PSG family appears to have undergone less expansion than the mouse, exhibits lower divergence rates and increased sequence homogenisation in the CFG face of the N1 domain. In contrast to most primate PSG N domains, rodent PSG N1 domains do not contain an RGD tri-peptide motif, but do contain RGD-like sequences, which are not conserved in rodent N2 and N3 domains.
Relative conservation of primate N domains and rodent N1 domains suggests that, despite independent gene family expansions and structural diversification, mouse and human PSGs retain conserved functions. Human PSG gene family expansion and homogenisation suggests that evolution occurred in a concerted manner that maintains similar functions of PSGs, whilst increasing gene dosage of the family as a whole. In the mouse, gene family expansion, coupled with local diversification of the CFG face, suggests selection both for increased gene dosage and diversification of function. Partial conservation of RGD and RGD-like tri-peptides in primate and rodent N and N1 domains, respectively, supports a role for these motifs in PSG function.

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    • "The presence of the tripeptide motif Arg-Gly-Asp (RGD) on an exposed loop of the N-domain of most human PSG proteins suggests that at least some of their functions may be mediated through integrin binding [6]. Snake venoms contain disintegrin proteins that bind integrins and disrupt cell - extracellular matrix interactions or blood clotting mechanisms and, analogously, we and others have hypothesised that PSGs may function as secreted integrin ligands that disrupt integrin function and thereby facilitate invasion of maternal tissues by fetal trophoblast, or disrupt other integrin mediated functions in maternal tissues [6], [24]. "
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    ABSTRACT: Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members encoded by multigene families in rodents and primates. In human pregnancy, PSGs are secreted by the syncytiotrophoblast, a fetal tissue, and reach a concentration of up to 400 ug/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGFβ1 from monocytes, macrophages, and other cell types, suggesting an immunoregulatory function. RGD tri-peptide motifs in the majority of human PSGs suggest that they may function like snake venom disintegrins, which bind integrins and inhibit interactions with ligands. We noted that human PSG1 has a KGD, rather than an RGD motif. The presence of a KGD in barbourin, a platelet integrin αIIbβ3 antagonist found in snake venom, suggested that PSG1 may be a selective αIIbβ3 ligand. Here we show that human PSG1 binds αIIbβ3 and inhibits the platelet - fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit αIIbβ3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent families. Our results suggest that in species with haemochorial placentation, in which maternal blood is in direct contact with fetal trophoblast, the high expression level of PSGs reflects a requirement to antagonise abundant (3 mg/ml) fibrinogen in the maternal circulation, which may be necessary to prevent platelet aggregation and thrombosis in the prothrombotic maternal environment of pregnancy.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Domain organization of mammalian carcinoembryonic antigen (CEA) family members. The domain organization of CEA family members from selected species was predicted by gene analysis and confirmed, where available, by EST (cattle) and cDNA sequences [4,5,27,35]. The conserved members are shown in green, members expressed predominantly in trophoblast cells of the placenta in grey boxes. "
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    ABSTRACT: Most rapidly evolving gene families are involved in immune responses and reproduction, two biological functions which have been assigned to the carcinoembryonic antigen (CEA) gene family. To gain insights into evolutionary forces shaping the CEA gene family we have analysed this gene family in 27 mammalian species including monotreme and marsupial lineages. Phylogenetic analysis provided convincing evidence that the primordial CEA gene family in mammals consisted of five genes, including the immune inhibitory receptor-encoding CEACAM1 (CEA-related cell adhesion molecule) ancestor. Our analysis of the substitution rates within the nucleotide sequence which codes for the ligand binding domain of CEACAM1 indicates that the selection for diversification is, perhaps, a consequence of the exploitation of CEACAM1 by a variety of viral and bacterial pathogens as their cellular receptor. Depending on the extent of the amplification of an ancestral CEACAM1, the number of CEACAM1-related genes varies considerably between mammalian species from less than five in lagomorphs to more than 100 in bats. In most analysed species, ITAM (immunoreceptor tyrosine-based activation motifs) or ITAM-like motif-containing proteins exist which contain Ig-V-like, ligand binding domains closely related to that of CEACAM1. Human CEACAM3 is one such protein which can function as a CEACAM1 decoy receptor in granulocytes by mediating the uptake and destruction of specific bacterial pathogens via its ITAM-like motif. The close relationship between CEACAM1 and its ITAM-encoding relatives appears to be maintained by gene conversion and reciprocal recombination. Surprisingly, secreted CEACAMs resembling immunomodulatory CEACAM1-related trophoblast-specific pregnancy-specific glycoproteins (PSGs) found in humans and rodents evolved only in a limited set of mammals. The appearance of PSG-like genes correlates with invasive trophoblast growth in these species. These phylogenetic studies provide evidence that pathogen/host coevolution and a possible participation in fetal-maternal conflict processes led to a highly species-specific diversity of mammalian CEA gene families.
    Full-text · Article · Feb 2010 · BMC Biology
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    • "Human PSG1, PSG4, PSG8 contain RGD-like tripeptides, namely, GDD, RRD, GGD, correspondingly (Table 3). These RGD-like motifs are arisen by transition and transversion events during the evolution [12]. No rodent PSG isolated to date possesses an RGD domain. "
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    ABSTRACT: Pregnancy-specific glycoproteins (PSGs) are secreted proteins which are produced by the rodent and primate placenta and play a critical role in pregnancy success. Genes which encode PSGs belong to carcinoembryonic antigen (CEA) gene family, which is included in immunoglobulin (Ig) gene superfamily. In humans, to date there are 11 protein products of these genes which are designated as PSG1-11. In rodents there are 17 PSGs, which are designated as PSG16-32. Human PSGs were first discovered in serum of pregnant women and were initially named as trophoblast-specific beta globulins (TBGs). Little later they were isolated from placental extracts and also revealed in serum of patients with trophoblastic tumors. Biological role of PSGs is not fully elucidated to date. However a number of experimental data and clinical observations allow supposing their critical role in the maintenance of pregnancy. Low PSG levels in the maternal circulation are associated with threatened abortions, intrauterine retardation and fetal hypoxia. It has been shown that PSGs function as immunomodulatory proteins which regulate activity of T-lymphocytes and secretion of cytokines by monocytes and macrophages. Also, PGSs may participate in maternal vasculature remodeling through influencing on secretion of proangiogenic agents such as transforming growth factor-beta-1 (TGF-ß1) and vascular endothelial growth factor (VEGF) by different cell types involved in the development of placenta. Several functional domains have been described in PSG structures. For example, tripeptide RGD has been revealed in N-terminal immunoglobulin (Ig)-like domain of most of human PSGs. It is proposed that RGD motif of PSGs is involved in binding to integrin receptors. Binding of mouse PSGs to integrin-associated receptor CD9 has been demonstrated. In our laboratory some human PSG-derived oligopeptide fragments have been shown to possess biological activity. This chapter is devoted to summarizing and analyzing of data on structure and function of PSGs known to date. Also, relatively recent data of PSG-derived biologically active peptides are described.
    Full-text · Article · Jan 2010
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