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J. Biol. Chem., Vol. 278, Issue 22, 20381-20388, May 30, 2003

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Two Aromatic Residues in the PB2 Subunit of Influenza A RNA Polymerase Are Crucial for Cap Binding^*

Pierre Fechter , Louise Mingay, Jane Sharps, Anna Chambers, Ervin Fodor  and George G. Brownlee  ¶

From the Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom

mRNAs are capped at their 5'-end by a unique cap structure containing N⁷-methyl guanine. Recognition of the cap structure is of paramount importance in some of the most central processes of gene expression as well as in some viral processes, such as priming of influenza virus transcription. The recent resolution of the structure of three evolutionary unrelated cap binding proteins, the vaccinia viral protein VP39, the eukaryotic translation factor eIF4E, and the nuclear cap-binding protein CBP20 showed that the recognition of the cap structure is achieved by the same general mechanism, i.e. by "sandwiching" of the N⁷-methyl guanine of the cap structure between two aromatic amino acid residues. The purpose of the present study was to test whether a similar cap recognition mechanism had independently evolved for the RNA polymerase of influenza virus. Combining in vivo and in vitro methods, we characterized two crucial aromatic amino acids, Phe³⁶³ and Phe⁴⁰⁴, in the PB2 subunit of the viral RNA polymerase that are essential for cap binding. The aromaticity of these two residues is conserved in influenza A, B, and C and even in the divergent Thogoto virus PB2 subunits. Thus, our results favor a similar mechanism of cap binding by the influenza RNA polymerase as in the evolutionary unrelated VP39, eIF4E, and CBP20.

Received for publication, January 7, 2003 , and in revised form, March 13, 2003.

^* 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.

Supported by Medical Research Council (MRC) Component Grant G9901312.

Supported by MRC Senior Nonclinical Fellowship G117/457.

^¶ To whom correspondence should be addressed. Tel.: 44-1865-275559; Fax: 44-1865-275556; E-mail: George.Brownlee{at}path.ox.ac.uk.

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