JVI Accepts, published online ahead of print on 10 October 2007

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J. Virol. doi:10.1128/JVI.01785-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A NOVEL ZINC-BINDING DOMAIN IS ESSENTIAL FOR FORMATION OF THE FUNCTIONAL JUNÍN VIRUS ENVELOPE GLYCOPROTEIN COMPLEX

Joanne York and Jack H. Nunberg^*

Montana Biotechnology Center, The University of Montana, Missoula, MT 59812

^* To whom correspondence should be addressed. Email: jack.nunberg{at}umontana.edu.

The envelope glycoprotein of the Junín arenavirus (GP-C) mediates entry into target cells through a pH-dependent membrane fusion mechanism. Unlike other Class I viral fusion proteins, the mature GP-C complex retains a cleaved, 58-amino-acid signal peptide (SSP) as an essential subunit, required both for trafficking of GP-C to the cell surface and for the activation of membrane fusion. SSP has been shown to associate non-covalently in GP-C via the cytoplasmic domain (CTD) of the transmembrane fusion subunit G2. In this report we investigate the molecular basis for this intersubunit interaction. We identify an invariant series of six cysteine and histidine residues in the CTD of G2 that is essential for incorporation of SSP in the GP-C complex. Moreover, we show that a CTD peptide fragment containing His-447, His-449 and Cys-455 specifically binds Zn⁺² at sub-nanomolar concentrations. Together, these results suggest a zinc finger-like domain structure in the CTD of G2. We propose that the remaining residues in the series (His-459, Cys-467 and Cys-469) form an intersubunit zinc-binding center that incorporates Cys-57 of SSP. This unusual motif may act to retain SSP in the GP-C complex and position the ectodomain loop of SSP for its role in modulating membrane-fusion activity. The unique tripartite organization of GP-C could provide novel molecular targets for therapeutic intervention in arenaviral disease.

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