A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.
The SARS-CoV-2 papain-like protease (PLpro) is a target for antiviral drug development. It is essential for processing viral polyproteins for replication and functions in host immune evasion by cleaving ubiquitin (Ub) and ubiquitin-like protein (Ubl) conjugates. While highly conserved, SARS-CoV-2 and SARS-CoV PLpro have contrasting Ub/Ubl substrate preferences. Using a ... combination of structural analyses and functional assays, we identify a molecular sensor within the S1 Ub-binding site of PLpro that serves as a key determinant of substrate specificity. Variations within the S1 sensor specifically alter cleavage of Ub substrates but not of the Ubl interferon-stimulated gene 15 protein (ISG15). Significantly, a variant of concern associated with immune evasion carries a mutation in the S1 sensor that enhances PLpro activity on Ub substrates. Collectively, our data identify the S1 sensor region as a potential hotspot of variability that could alter host antiviral immune responses to newly emerging SARS-CoV-2 lineages.
Mesh Terms:
Amino Acid Sequence, Binding Sites, COVID-19, Coronavirus Papain-Like Proteases, HEK293 Cells, Humans, Papain, Peptide Hydrolases, Protein Binding, SARS-CoV-2, Substrate Specificity, Ubiquitin, Ubiquitins, Viral Proteins
Amino Acid Sequence, Binding Sites, COVID-19, Coronavirus Papain-Like Proteases, HEK293 Cells, Humans, Papain, Peptide Hydrolases, Protein Binding, SARS-CoV-2, Substrate Specificity, Ubiquitin, Ubiquitins, Viral Proteins
Cell Rep
Date: Dec. 28, 2020
PubMed ID: 34547223
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