A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.
Cell Rep
; 36(13): 109754, 2021 09 28.
Article
in English
| MEDLINE | ID: covidwho-1401298
ABSTRACT
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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Cell Rep
Year:
2021
Document Type:
Article
Affiliation country:
J.celrep.2021.109754
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