A STRUCTURAL MODEL OF PICORNAVIRUS LEADER PROTEINASES BASED ON PAPAINAND BLEOMYCIN HYDROLASE

The leader (L) proteinases of aphthoviruses (foot-and-mouth disease vi ruses) and equine rhinovirus serotypes 1 and 2 cleave themselves from the growing polyprotein. This cleavage occurs intramolecularly between the C terminus of the L proteinases and the N terminus of the subsequ ent protein VP4, The foot-and-mouth disease virus enzyme has been show n, in addition, to cleave at least one cellular protein, the eukaryoti c initiation factor 4G, Mechanistically, inhibitor studies and sequenc e analysis have been used to classify the L proteinases as papain-like cysteine proteinases, However, sequence identity within the L protein ases themselves is low (between 18% and 32%) and only 14% between the L proteinases and papain, Secondary structure predictions, sequence al ignments that take into account the positions of the essential catalyt ic residues, and structural considerations have been used in this stud y to investigate more closely the relationships between the L proteina ses and papain, In spite of the low sequence identities, the analyses strongly suggest that the L proteinases of foot-and-mouth disease viru s and of equine rhinovirus 1 have a similar overall fold to that of pa pain, Regions in the L proteinases corresponding to all five alpha-hel ices and seven beta-sheets of papain could be identified, Further comp arisons with the proteinase bleomycin hydrolase, which also displays a papain topology in spite of important differences in size and amino a cid sequence, support these conclusions and suggest how a C-terminal e xtension, present in all three L proteinases, and predicted to be an a lpha-helix, might enable C-terminal self-processing to occur.