Residue L143 of the foot-and-mouth disease virus leader proteinase is a determinant of cleavage specificity

The foot-and-mouth disease virus (FMDV) leader proteinase (L-pro) self-processes inefficiently at the L-pro/VP4 cleavage site LysLeuLys*GlyAlaGly (* indicates cleaved peptide bond) when the leucine at position P2 is replaced by phenylalanine. Molecular modeling and energy minimization identified the L-pro residue L143 as being responsible for this discrimination. The variant L-pro L143A self-processed efficiently at the L-pro/VP4 cleavage site containing P2 phenylalanine, whereas the L143M variant did not. L-pro L143A self-processing at the eIF4GII sequence AspPbeGly*ArgGlnThr was improved but showed more-extensive aberrant processing. Residue 143 in L-pro is occupied only by leucine and methionine in all sequenced FMDV serotypes, implying that these bulky side chains are one determinant of the restricted specificity of L-pro.