The non-structural proteins of foot-and-mouth disease virus (FMDV) are responsible for
RNA replication, proteolytic processing of the viral polyprotein precursor, folding and
assembly of the structural proteins and modification of the cellular translation apparatus.
Investigation of the amino acid heterogeneity of the non-structural proteins of seventy-
nine FMDV isolates of SAT1, SAT2, SAT3, A and O serotypes revealed between 29 and 62%
amino acid variability. The Leader protease (Lpro) and 3A proteins were the most variable
whilst the RNA-dependent RNA polymerase (3Dpol) the most conserved. Phylogeny based
on the non-structural protein-coding regions showed separate clusters for southern
African viruses for both the Lpro and 3C protease (3Cpro) and sequences unique to this group
of viruses, e.g. in the 2C and 3Cpro proteins. These groupings were unlike serotype
groupings based on structural protein-coding regions. The amino acid substitutions and
the nature of the naturally occurring substitutions provide insight into the functional
domains and regions of the non-structural proteins that are critical for structure–function.
The Lpro of southern African SAT type isolates differed from A, O and SAT isolates in
northern Africa, particularly in the auto-processing region. Three-dimensional structures
of the 3C protease (3Cpro) and 3Dpol showed that the observed variation does not affect the
enzymatic active sites or substrate binding sites. Variation in the 3Cpro cleavage sites
demonstrates broad substrate specificity.