Pregnancy

Functional Characterization of the Placental Fusogenic Membrane Protein Syncytin

Abstract
Syncytin is an envelope protein of the human endogenous retrovirus family W (HERV-W). Syncytin is specifically expressed in the human placenta and mediates trophoblast cell fusion into the multinucleated syncytiotrophoblast layer. Syncytin is a polypeptide of 538 amino acids and is predicted to be post-translationally cleaved into a surface (SU) subunit and a transmembrane (TM) subunit. Functional characterization of syncytin protein can aid understanding of the molecular mechanism underlying syncytin-mediated cell fusion. In this report, we studied the structure-function relationship of syncytin in 293T and HeLa cells transiently expressing wild-type syncytin or syncytin mutants generated by linker-scanning and deletion mutagenesis. Of the 22 linker-inserted mutants, mutants InS(51), InV(139), InE(156), InS(493), InA(506), and InL(529) were fusogenic suggesting that regions around amino acids S⁵¹, V¹³⁹, and E¹⁵⁶ in the SU subunit and S⁴⁹³, A⁵⁰⁶, and L⁵²⁹ in the cytoplasmic domain (CTM) of syncytin are flexible in conformation. Of the 17 deletion mutants, nine mutants with deletions in the region from amino acids 479 to 538 were fusogenic. The deletion mutant DelI(480), containing only the first four amino acid residues in the cytoplasmic domain, had enhanced fusogenic activity in comparison with the wild-type. In addition, two heptad repeat regions (HRA and B) were defined in the TM subunit of syncytin. A peptide inhibitor derived from the C-terminal heptad repeat region (HRB) was shown to potently inhibit syncytin-mediated cell fusion. Our results suggest that the cytoplasmic domain of syncytin is not essential for syncytin-mediated fusion but may play a regulatory role, and an intramolecular interaction between HRA and B is involved in the fusion process.

Key words: Pregnancy • Placenta • Syncytiotrophoblast • Trophoblast

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