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Papain-like protease (PLpro) is a viral cysteine protease that plays a key role in the viral life cycle, by cleaving non-structural proteins from polyproteins encoded by RNA. PLpro also has deubiquitinating activity and may act on host proteins to interfere with the host immune response.
Papain-like protease (PLpro) is a 35kDa cysteine protease found in coronaviruses that is important in viral replication. This enzyme is a functional monomer with four structural domains named finger, palm, thumb and ubiquitin-like. The active site is located at the interface of the palm and thumb domains. Sequence modelling suggests the PLpro has 6 transmembrane domains towards the c-terminal, and a long tail that extends into the cytoplasm. Although the structure of the active site is highly conserved between PLpro from SARS-COV and SARS-CoV-2, the full-length enzymes share only 85% sequence identity. In comparison, both SARS-COV and SARS-CoV-2 PLpro share poor sequence identity with MERS-CoV PLpro, with only 34% and 33% similarity, respectively.
An essential function of PLpro is to release non-structural proteins from the polyproteins that are encoded by coronavirus mRNA, together with 3C-like protease (3CLpro, also known as Mpro). PLpro cleaves polyprotein 1a at three sites, while Mpro cleaves both polyproteins 1a and 1b at a total of 11 sites. Although most coronaviruses express a single PLpro, some viruses including mouse hepatitis virus and human CoV-229E are thought to have two forms.
In addition to its action on viral polyproteins, PLpro can also reverse the post-translational ubiquitination and ISGylation of host proteins. Both modifications are important in host immune responses, where they are associated with stimulation of NF-κB-mediated inflammation, interferon responses, as well as the production of cytokines and chemokines. PLpro from different coronaviruses may have differing preferences for modified proteins; SARS-CoV PLpro is more active against ubiquitinated proteins, while SARS-CoV-2 PLpro preferentially acts on ISGylated substrates.
Figure 1: Structure of PLpro from MERS. Structure taken from Protein Data Bank, PDBID: 4REZ. Bailey-Elkin et al (2014) Crystal Structure of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Papain-like Protease Bound to Ubiquitin Facilitates Targeted Disruption of Deubiquitinating Activity to Demonstrate Its Role in Innate Immune Suppression. J Biol Chem 289: 34667-34682