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

Stephanie Patchett, Zongyang Lv, Wioletta Rut, Miklos Békés, Marcin Drag, Shaun K. Olsen, Tony T. Huang

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Article number109754
JournalCell Reports
Volume36
Issue number13
DOIs
StatePublished - Sep 28 2021

Keywords

  • COVID-19
  • DUB
  • ISG15
  • K48-linked Ub
  • PLpro
  • SARS-CoV-1
  • SARS-CoV-2
  • coronavirus
  • cysteine protease
  • deubiquitinase
  • papain-like protease
  • ubiquitin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease'. Together they form a unique fingerprint.

Cite this