ERVFRD-1, ERVFRDE1, GLLL6191, HERV-FRD, HERV-W/FRD, UNQ6191, envFRD, endogenous retrovirus group FRD member 1, endogenous retrovirus group FRD member 1, envelope
Syncytin-2 also known as endogenousretrovirus group FRD member 1 is a protein that in humans is encoded by the HERV-FRD family, also known as the ERVFRD-1 gene.[5][6] This gene, "Is part of a human endogenous retrovirus provirus on chromosome 6-".[7] Both Syncytin-2 and Syncytin-1 are encoded by ENV genes and were first identified in a human placenta.[8] Specifically, Syncytin-2 was observed in the cytoplasmic membrane of primary trophoblast cells in the placenta.[6]
The receptor for this fusogenicenv protein is ASCT-2 and the transporter is MFSD-2.[9][10] In studies conducted that observed the protein interactions with this receptor, it was additionally found that Syncytin-2 signals were detected at the membrane.[6] This is a place of, "Cell-to-cell contact" where this protein can interact with its receptor, in order to be able to induce fusion.[6]
General Genomic Structure of HERVs
Structure
Syncytin-2 consists of a crystal structure and forms a post-fusion 6-helix bundle structure.[11][12] It, "Encodes a 59kDa polypeptide-" and shares similar structural organization in, "Present-day retroviral envelopes-". [13]This protein also has a cleavage site that is used to separate the surface and the transmembrane proteins.[14] The surface subunit binds to an unidentified receptor on the transmembrane subunit of a target cell. [13] In this transmembrane subunit, it consists of "An N-terminal fusion peptide, an ectodomain including a leucine zipper motif, a highly hydrophobic transmembrane anchor, and a C-terminal intracellular domain-".[13]
In both Syncytin-2 and Syncytin-1, in their structures, the env gene is complete and able to encode for fusogenic activity, but their gag and pol genes are disrupted. [13] In this case, the gag and pol genes serve to accumulate inhibitory mutations in order to allow the gag gene to, "Encode for structural viral proteins-" and for the pol gene to encode for viral enzymes.[15] While env genes, due to their fusogenic activity, are now used to for reproduction and placentation benefits.[15]
Function
The role of this protein is key in the implantation of human embryos in the womb, placental formation, syncytium formation, possibly apoptosis, and the regulation of syncytiotrophoblast creation.[6][16][14]
Syncytins as a whole are primarily expressed in the placenta and the formation of syncytium is conducted by syncytin one and two, with their genes primarily being expressed in trophoblasts.[2] Their fusogenic activity, which originally served to favor cell fusion of a virus, now serves to develop the placental syncytiotrophoblast.[6]
In regard to the regulation of syncytiotrophoblast regulation, the role of Syncytin-2 has not been definitively defined especially for the early phases of placental development, however, this protein is the most serious candidate in comparison to Syncytin-1.[6][17] Through research conducted on this protein, due to the fact that it is only expressed in placental tissue, as well as having a good fusogenic capacity, speculation is pointing to this protein playing a significant role in this regulation earlier on in the developmental process.[17]
There has been research that demonstrates that lower levels of syncytin gene expression and the pathogenesis of preeclampsia may be correlated.[6] For Syncytin-2 in particular, there is a reduced amount of gene expression for this protein in pregnant women with preeclampsia compared to those who were healthy.[6] However, there is no exact role established in the pathogenesis of preeclampsia for syncytins, and most data so far is correlative or hypothetical.
Similarly, the exact influence of syncytins in tumorigenesis is also uncertain, but it is hypothesized that the tumor development may persist due to their fusogenecity.[6]
Further studies need to be conducted for multiple sclerosis and gestational diabetes, as well as these other diseases to either fully confirm their association or deny those with less research or potentially inaccurate hypothesis. [6]
Evolution
This gene is conserved among all primates, with an estimated age of 45 million years, and entered the primate genome before Syncytin-1.[8] Specifically, this protein entered the genome, "Before the split between New World and Old-World Monkeys".[17] However, this protein is absent in prosimians.[13] Due to its open reading frame, "Low mutation rate, and a low level of polymorphism among humans-", this gene has persisted.[18] Indicating its significance in mammalian evolution and the potential benefits to reproductive functions given this conservation.[8]
The mouse syncytins are not true orthologues.[19] In mice, they are syncytin-A and syncytin-B, and are unrelated to the human syncytin one and two, and entered the lineage 20 million plus years ago.[9] However, because of their similar functions, it is hypothesized that the capture of these retroviral envelope genes, could have potentially played as a factor in the emergence of placental mammals altogether. [20]
The virus, along with some very similar insertions, belong to a group under the Gammaretrovirus-like class I ERVs. Similar ERVs are found in artiodactyls, a result of an independent integration event.[21] A proposed nomenclature suggests putting all such "class I" elements in a genus-level taxon separate from Gammaretrovirus.[22]
123Soygur B, Sati L (November 2016). "The role of syncytins in human reproduction and reproductive organ cancers". Reproduction. 152 (5): R167 –R178. doi:10.1530/rep-16-0031. PMID27486264.
↑Renard M, Varela PF, Letzelter C, Duquerroy S, Rey FA, Heidmann T (October 2005). "Crystal structure of a pivotal domain of human syncytin-2, a 40 million years old endogenous retrovirus fusogenic envelope gene captured by primates". Journal of Molecular Biology. 352 (5): 1029–1034. doi:10.1016/j.jmb.2005.07.058. PMID16140326.
12345Renard M, Varela PF, Letzelter C, Duquerroy S, Rey FA, Heidmann T (October 2005). "Crystal structure of a pivotal domain of human syncytin-2, a 40 million years old endogenous retrovirus fusogenic envelope gene captured by primates". Journal of Molecular Biology. 352 (5): 1029–1034. doi:10.1016/j.jmb.2005.07.058. PMID16140326.
12Cardoso, R., Martins Cardoso, R., Oude Blenke, E., & Mastrobattista, E. (n.d.). SYNCYTINS Retroviral proteins with potential role in the development of drug delivery systems. Syncytins: retroviral proteins with potential role in the development of drug delivery systems. Retrieved November 23, 2025, from https://studenttheses.uu.nl/bitstream/handle/20.500.12932/17960/Thesis%20Renata%20Martins%20Cardoso%203942287.pdf?sequence=2
↑Vargas A, Moreau J, Landry S, LeBellego F, Toufaily C, Rassart E, etal. (September 2009). "Syncytin-2 plays an important role in the fusion of human trophoblast cells". Journal of Molecular Biology. 392 (2): 301–318. doi:10.1016/j.jmb.2009.07.025. PMID19616006.
Renard M, Varela PF, Letzelter C, Duquerroy S, Rey FA, Heidmann T (October 2005). "Crystal structure of a pivotal domain of human syncytin-2, a 40 million years old endogenous retrovirus fusogenic envelope gene captured by primates". Journal of Molecular Biology. 352 (5): 1029–1034. doi:10.1016/j.jmb.2005.07.058. PMID16140326.
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