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J. Biol. Chem., Vol. 276, Issue 38, 35473-35481, September 21, 2001

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Foot-and-Mouth Disease Virus Leader Proteinase
INVOLVEMENT OF C-TERMINAL RESIDUES IN SELF-PROCESSING AND CLEAVAGE OF eIF4GI^*

Walter Glaser, Regina Cencic, and Tim Skern^§

From the Institute of Medical Biochemistry, Division of Biochemistry, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9/3, A-1030 Vienna, Austria

The leader proteinase (L^pro) of foot-and-mouth disease virus frees itself from the nascent polyprotein, cleaving between its own C terminus and the N terminus of VP4 at the sequence Lys-Leu-Lys--Gly-Ala-Gly. Subsequently, the L^pro impairs protein synthesis from capped mRNAs in the infected cell by processing a host protein, eukaryotic initiation factor 4GI, at the sequence Asn-Leu-Gly--Arg-Thr-Thr. A rabbit reticulocyte lysate system was used to examine the substrate specificity of L^pro and the relationship of the two cleavage reactions. We show that L^pro requires a basic residue at one side of the scissile bond to carry out efficient self-processing. This reaction is abrogated when leucine and lysine prior to the cleavage site are substituted by serine and glutamine, respectively. However, the cleavage of eIF4GI is unaffected by the inhibition of self-processing. Removal of the 18-amino acid C-terminal extension of L^pro slowed eIF4GI cleavage; replacement of the C-terminal extension by unrelated amino acid sequences further delayed this cleavage. Surprisingly, wild-type L^pro and the C-terminal variants all processed the polyprotein cleavage site in an intermolecular reaction at the same rate. However, when the polyprotein cleavage site was part of the same polypeptide chain as the wild-type Lb^pro, the rate of processing was much more rapid. These experiments strongly suggest that self-processing is an intramolecular reaction.

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