A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease

A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease

Blog Article

Summary: The SARS-CoV-2 papain-like protease (PLpro) is a target for antiviral drug development.It is essential for equi-jec 7 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 abc material 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.