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The binding of foot‐and‐mouth disease virus leader proteinase to eIF4GI involves conserved ionic interactions
Author(s) -
Foeger Nicole,
Kuehnel Elisabeth,
Cencic Regina,
Skern Tim
Publication year - 2005
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2005.04689.x
Subject(s) - binding site , biochemistry , chemistry , foot and mouth disease virus , internal ribosome entry site , eif4e , biology , ribosome , virus , virology , rna , translation (biology) , messenger rna , gene
The leader proteinase (L pro ) of foot‐and‐mouth disease virus (FMDV) initially cleaves itself from the polyprotein. Subsequently, L pro cleaves the host proteins eukaryotic initiation factor (eIF) 4GI and 4GII. This prevents protein synthesis from capped cellular mRNAs; the viral RNA is still translated, initiating from an internal ribosome entry site. L pro cleaves eIF4GI between residues G674 and R675. We showed previously, however, that L pro binds to residues 640–669 of eIF4GI. Binding was substantially improved when the eIF4GI fragment contained the eIF4E binding site and eIF4E was present in the binding assay. L pro interacts with eIF4GI via residue C133 and residues 183–195 of the C‐terminal extension. This binding domain lies about 25 Å from the active site. Here, we examined the binding of L pro to eIF4GI fragments generated by in vitro translation to narrow the binding site down to residues 645–657 of human eIF4GI. Comparison of these amino acids with those in human eIF4GII as well as with sequences of eIF4GI from other organisms allowed us to identify two conserved basic residues (K646 and R650). Mutation of these residues was severely detrimental to L pro binding. Similarly, comparison of the sequence between residues 183 and 195 of L pro with those of other FMDV serotypes and equine rhinitis A virus showed that acidic residues D184 and E186 were highly conserved. Substitution of these residues in L pro significantly reduced eIF4GI binding and cleavage without affecting self‐processing. Thus, FMDV L pro has evolved a domain that specifically recognizes a host cell protein.