Deubiquitination, a New Function of the Severe Acute Respiratory Syndrome Coronavirus Papain-Like Protease?

Abstract

A new coronavirus has been identified as the infectious agent of severe acute respiratory syndrome (SARS). Although SARS was successfully contained by quarantine measures, the reconstructed itinerary of the virus through 30 countries and its high mortality rate illustrate the global threat that this newly emerging disease represents (17). During the expression of the SARS coronavirus (SCoV) genome, two viral cysteine proteases, a papain-like protease (PLpro) and a chymotrypsin-like protease (3CLpro), process the encoded polyprotein precursor to release most of the proteins required for virus replication. PLpro refers to a domain of nonstructural protein 3, whose boundaries are defined by homology to the papain-like fold (7). The PLpro domain can be regarded as the catalytic core behind PLpro-mediated cleavages, even though processing by PLpros has been reported to be modulated by additional amino acid residues outside of these boundaries (15, 18). The SCoV utilizes a single PLpro, whereas most coronaviruses contain two paralogous enzymes, termed PL1pro and PL2pro (14). PLpros in general are not as well characterized as 3CLpros and have not generated as much interest as pharmaceutical targets. However, further structure-to-function annotations might refocus the attention on PLpros. For this purpose, we mined the current Protein Data Bank (PDB) content using the Structure Prediction Meta Server (http://www.bioinfo.pl/meta ), which assembles state-of-the-art fold recognition methods and provides a consensus sequence-to-structure hyperscore with the 3D-Jury method (4). The only highly reliable prediction (3D-Jury score > 100) obtained for the SCoV PLpro sequence from K1632 to E1847 was the structure of the catalytic core domain of the herpesvirus-associated ubiquitin-specific protease (HAUSP), also known as USP7 (8).