Comparison of self-processing of foot-and-mouth disease virus leader proteinase and porcine reproductive and respiratory syndrome virus leader proteinase nsp1α

Abstract

The foot-and-mouth disease virus leader proteinase (Lb(pro)) cleaves itself off the nascent viral polyprotein. NMR studies on the monomeric variant Lb(pro) L200F provide structural evidence for intramolecular self-processing. (15)N-HSQC measurements of Lb(pro) L200F showed specifically shifted backbone signals in the active and substrate binding sites compared to the monomeric variant sLb(pro), lacking six C-terminal residues. This indicates transient intramolecular interactions between the C-terminal extension (CTE) of one molecule and its own active site. Contrastingly, the porcine reproductive and respiratory syndrome virus (PRRSV) leader proteinase nsp1α, with a papain-like fold like Lb(pro), stably binds its own CTE. Parts of the β-sheet domains but none of the α-helical domains of Lb(pro) and nsp1α superimpose; consequently, the α-helical domain of nsp1α is oriented differently relative to its β-sheet domain. This provides a large interaction surface for the CTE with the globular domain, stabilising the intramolecular complex. Consequently, self-processing inactivates nsp1α but not Lb(pro).

Keywords: Active site; C-terminal extension; CTE; FMDV; Foot-and-mouth disease virus; Lb(pro); Leader proteinase; Non-structural protein; PRRSV; Papain-like cysteine proteinase; Polyprotein processing; Porcine reproductive and respiratory syndrome virus; Protein fold; Shortened leader proteinase (lacking 6 C-terminal amino acids); Substrate binding; Wildtype; nsp; sLb(pro); wt.