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J. Biol. Chem., Vol. 278, Issue 35, 33200-33207, August 29, 2003

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Human Rhinovirus 2 2A^pro Recognition of Eukaryotic Initiation Factor 4GI

INVOLVEMENT OF AN EXOSITE^*

Nicole Foeger , Eva M. Schmid  and Tim Skern 

From the Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Division of Biochemistry, University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/3, A-1030 Vienna, Austria

The 2A proteinase (2A^pro) of human rhinovirus 2 is a cysteine proteinase with a unique chymotrypsin-like fold. During viral replication, 2A^pro performs self-processing by cleaving between its own N terminus and the C terminus of the preceding protein, VP1. Subsequently, 2A^pro cleaves the two isoforms of the cellular protein, eukaryotic initiation factor (eIF) 4G. We have previously shown that HRV2 2A^pro can directly bind to eIF4G isoforms. Here we demonstrate using deletion mutants of eIF4GI that HRV2 2A^pro requires eIF4GI amino acids 600–674 for binding; however, the amino acids at the cleavage site, Arg⁶⁸¹ Gly, are not required. The HRV2 2A^pro binding domain for eIF4GI was identified by site-directed mutagenesis. Specifically, mutations Leu¹⁷ Arg and Asp³⁵ Glu severely impaired HRV2 2A^pro binding and thus processing of eIF4GI in rabbit reticulocyte lysates; self-processing, however, was not affected. Alanine scanning analysis further identified the loop containing residues Tyr³², Ser³³, and Ser³⁴ as important for eIF4GI binding. Although Asp³⁵ is part of the catalytic triad, most of the eIF4GI binding domain lies in a unique exosite structure absent from other chymotrypsin-like enzymes and is distinct from the substrate binding cleft. The exosite represents a novel virulence determinant that may allow the development of specific inhibitors for HRV2 2A^pro.

Received for publication, April 16, 2003 , and in revised form, June 3, 2003.

^* This work was supported by Grant P-16189 from the Austrian Science Foundation (to T. S.). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 43-1-4277-61620; Fax: 43-1-4277-9616; E-mail: timothy.skern{at}univie.ac.at.

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