Pregnancy-specific glycoproteins bind integrin alpha IIb beta 3 and inhibit the platelet-fibrinogen interaction

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Shanley, Daniel K.
Kiely, Patrick A.
Golla, Kalyan
Allen, Seamus
Martin, Kenneth
O'Riordan, Ronan T.
Ball, Melanie
Aplin, John D.
Singer, Bernhard B.
Caplice, Noel M.
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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 mu g/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGF beta 1 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 alpha IIb beta 3 antagonist found in snake venom, suggested that PSG1 may be a selective alpha IIb beta 3 ligand. Here we show that human PSG1 binds alpha IIb beta 3 and inhibits the platelet - fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit alpha IIb beta 3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent PSG 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.
Alternative activation , Expression , Preeclampsia , Proteins , Coagulation , Secretion , Monocytes , Markers , Cells , PSG
Shanley DK, Kiely PA, Golla K, Allen S, Martin K, O’Riordan RT, et al. (2013) Pregnancy-Specific Glycoproteins Bind Integrin αIIbβ3 and Inhibit the Platelet—Fibrinogen Interaction. PLoS ONE 8(2): e57491. doi:10.1371/journal.pone.0057491