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J. Biol. Chem., Vol. 281, Issue 38, 28232-28243, September 22, 2006

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Structure-Function Analysis of the Coxsackievirus Protein 3A

IDENTIFICATION OF RESIDUES IMPORTANT FOR DIMERIZATION, VIRAL RNA REPLICATION, AND TRANSPORT INHIBITION^*

Els Wessels, Richard A. Notebaart, Daniël Duijsings, Kjerstin Lanke, Bart Vergeer, Willem J. G. Melchers, and Frank J. M. van Kuppeveld¹

From the Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands and the Center for Molecular and Biomolecular Informatics, University of Nijmegen, 6500 GL Nijmegen, The Netherlands

The coxsackievirus B3 3A protein forms homodimers and plays important roles in both viral RNA (vRNA) replication and the viral inhibition of intracellular protein transport. The molecular determinants that are required for each of these functions are yet poorly understood. Based on the NMR structure of the closely related poliovirus 3A protein, a molecular model of the coxsackievirus B3 3A protein was constructed. Using this structural model, specific mutants were designed to study the structure-function relationship of 3A. The mutants were tested for their capacity to dimerize, support vRNA replication, and block protein transport. A hydrophobic interaction between the monomers and an intermolecular salt bridge were identified as major determinants required for dimerization. We show that dimerization is important for both efficient vRNA replication and inhibition of protein transport. In addition, determinants were identified that were not required for dimerization but that were essential for either one of the biological functions of 3A. The combination of the in silico and in vivo results obtained in this study provides important insights in both the structural and functional aspects of 3A.

Received for publication, February 6, 2006 , and in revised form, July 18, 2006.

^* This work was supported in part by Netherlands Organization for Scientific Research Grant NWO-VIDI-917.46.305, a grant from the M. W. Beijerink Virology Fund from the Royal Netherlands Academy of Sciences, and European Communities Grant INTAS 2012. 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 supplemental Table S1.

¹ To whom correspondence should be addressed: Dept. of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 31-24-3617574; Fax: 31-24-3614666; E-mail: f.vankuppeveld{at}ncmls.ru.nl.

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