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Mapping the Landscape of the Lymphocytic Choriomeningitis Virus Stable Signal Peptide Reveals Novel Functional Domains

April A. Saunders,¹ Joey P. C. Ting,¹ Jeffrey Meisner,² Benjamin W. Neuman,^1, Mar Perez,¹ Juan Carlos de la Torre,¹ and Michael J. Buchmeier^1*

Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037,¹ Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322²

Received 14 December 2006/ Accepted 8 March 2007

The stable signal peptide (SSP) of the lymphocytic choriomeningitis virus surface glycoprotein precursor has several unique characteristics. The SSP is unusually long, at 58 amino acids, and contains two hydrophobic domains, and its sequence is highly conserved among both Old and New World arenaviruses. To better understand the functions of the SSP, a panel of point and deletion mutants was created by in vitro mutagenesis to target the highly conserved elements within the SSP. We were also able to confirm critical residues required for separate SSP functions by trans-complementation. Using these approaches, it was possible to resolve functional domains of the SSP. In characterizing our SSP mutants, we discovered that the SSP is involved in several distinct functions within the viral life cycle, beyond translocation of the viral surface glycoprotein precursor into the endoplasmic reticulum lumen. The SSP is required for efficient glycoprotein expression, posttranslational maturation cleavage of GP1 and GP2 by SKI-1/S1P protease, glycoprotein transport to the cell surface plasma membrane, formation of infectious virus particles, and acid pH-dependent glycoprotein-mediated cell fusion.

Published ahead of print on 21 March 2007.

Present address: University of Reading, Reading, Berkshire, United Kingdom.

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