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J. Biol. Chem., Vol. 279, Issue 49, 51386-51394, December 3, 2004

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Myristoylation, a Protruding Loop, and Structural Plasticity Are Essential Features of a Nonenveloped Virus Fusion Peptide Motif^*

Jennifer A. Corcoran, Raymond Syvitski¶, Deniz Top, Richard M. Epand||**, Raquel F. Epand||, David Jakeman, and Roy Duncan**

From the Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada, the College of Pharmacy, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada, and the ^||Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Members of the fusion-associated small transmembrane (FAST) protein family are a distinct class of membrane fusion proteins encoded by nonenveloped fusogenic reoviruses. The 125-residue p14 FAST protein of reptilian reovirus has an 38-residue myristoylated N-terminal ectodomain containing a moderately apolar N-proximal region, termed the hydrophobic patch. Mutagenic analysis indicated sequence-specific elements in the N-proximal portion of the p14 hydrophobic patch affected cell-cell fusion activity, independent of overall effects on the relative hydrophobicity of the motif. Circular dichroism (CD) of a myristoylated peptide representing the majority of the p14 ectodomain suggested this region is mostly disordered in solution but assumes increased structure in an apolar environment. From NMR spectroscopic data and simulated annealing, the soluble nonmyristoylated p14 ectodomain peptide consists of an N-proximal extended loop flanked by two proline hinges. The remaining two-thirds of the ectodomain peptide structure is disordered, consistent with predictions based on CD spectra of the myristoylated peptide. The myristoylated p14 ectodomain peptide, but not a nonmyristoylated version of the same peptide nor a myristoylated scrambled peptide, mediated extensive lipid mixing in a liposome fusion assay. Based on the lipid mixing activity, structural plasticity, environmentally induced conformational changes, and kinked structures predicted for the p14 ectodomain and hydrophobic patch (all features associated with fusion peptides), we propose that the majority of the p14 ectodomain is composed of a fusion peptide motif, the first such motif dependent on myristoylation for membrane fusion activity.

Received for publication, June 22, 2004 , and in revised form, September 1, 2004.

^* This research was supported by grants from the Canadian Institutes of Health Research (CIHR). 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.

^¶ A Killam Trust Foundation postdoctoral fellow.

^** Recipient of a CIHR Investigator Award.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Tupper Medical Bldg., Rm 7S, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada. Tel.: 902-494-6770; Fax: 902-494-5125; E-mail: roy.duncan{at}dal.ca.

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