Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications.

TLDR

Cysteine proteases encoded by animal picornaviruses and plant viruses are essential for virus maturation. The viral proteases replace Ser‑195 with Cys in the trypsin catalytic triad, and sequence alignment indicates that the twin β‑barrel trypsin fold is retained. These viral cysteine proteases are homologous to trypsin‑like serine proteases, with conserved His‑57 and Asp‑102, and their 2a and 3c subclasses correspond to the small and large trypsin‑like serine protease subclasses, allowing mapping of specificity‑determining residues.

Abstract

Proteases that are encoded by animal picornaviruses and plant comme- and potyviruses form a related group of cysteine-active-center enzymes that are essential for virus maturation. We show that these proteins are homologous to the family of trypsin-like serine proteases. In our model, the active-site nucleophile of the trypsin catalytic triad, Ser-195, is changed to a Cys residue in these viral proteases. The other two residues of the triad, His-57 and Asp-102, are otherwise absolutely conserved in all the viral protease sequences. Secondary structure analysis of aligned sequences suggests the location of the component strands of the twin beta-barrel trypsin fold in the viral proteases. Unexpectedly, the 2a and 3c subclasses of viral cysteine proteases are, respectively, homologous to the small and large structural subclasses of trypsin-like serine proteases. This classification allows the molecular mapping of residues from viral sequences onto related tertiary structures; we precisely identify amino acids that are strong determinants of specificity for both small and large viral cysteine proteases.