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J. Biol. Chem., Vol. 282, Issue 1, 381-389, January 5, 2007

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Functional Characterization of Syncytin-A, a Newly Murine Endogenous Virus Envelope Protein

IMPLICATION FOR ITS FUSION MECHANISM^*

From the State Key Laboratory of Virology and Modern Virology Research Centre, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China

Trophoblast fusion in placenta is an important event for preservation of a healthy pregnancy. This process takes place throughout the pregnancy and is crucial for the formation of syncytiotrophoblast layer. Syncytin-1 and syncytin-2 are strong candidate regulators of fusion from retroviral origin. Syncytin-A and syncytin-B are other candidates from retroviral origin in Muridae. The active role of syncytin in driving fusion of trophoblast has been identified, but its fusion mechanism is still unclear. As an intact retroviral envelope protein, syncytin-A shares similar structure profiling with other viral envelope fusion proteins, especially in the regions of N- and C-terminal heptad repeats (NHR and CHR, respectively). In this paper, we showed that SynA 1 + 2 of syncytin-A (residues 445-536, including predicted NHR, CHR, and a natural linker) could form trimer and exhibited significant -helix structure and high thermo-stability. Limited proteolysis result identified a stable protease-resistant core of SynA 1 + 2, which was in good agreement with computational modeling data. NHR and CHR could interact with each other in vitro, too. Different from the previous studies, the disulfide-bonded linker was apparently vital to the stability of fusion core structure. By biological assays, NHR was shown to be inhibitive to cell-cell fusion, with IC₅₀ value about 5.4 µM, but CHR seemed to have no inhibitory activity even at 50 µM. From both biochemical and functional data, we first gave an explanation how syncytin-A mediated cell fusion. The insight into the mechanism of syncytin-A-mediated cell-cell fusion may provide a crucial clue to placental cytotrophoblast morphogenesis.

Received for publication, July 5, 2006 , and in revised form, November 9, 2006.

^* This work was supported by grants from National Natural Science Foundation of China (Grant number 30570067) and the Outstanding Youth Foundation of HuBei Province, China (to G. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental data and a figure.

¹ To whom correspondence should be addressed. Fax: 86-27-68752897; E-mail: gxiao{at}whu.edu.cn.

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