tetano
Editor, Senior Moderator
Cell Rep
. 2021 Sep 8;109754.
doi: 10.1016/j.celrep.2021.109754. Online ahead of print.
A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease
Stephanie Patchett[SUP] 1 [/SUP], Zongyang Lv[SUP] 2 [/SUP], Wioletta Rut[SUP] 3 [/SUP], Miklos Békés[SUP] 1 [/SUP], Marcin Drag[SUP] 3 [/SUP], Shaun K Olsen[SUP] 4 [/SUP], Tony T Huang[SUP] 5 [/SUP]
Affiliations
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: COVID-19; DUB; ISG15; K48-linked Ub; PLpro; SARS-CoV-1; SARS-CoV-2; coronavirus; cysteine protease; deubiquitinase; papain-like protease; ubiquitin.
. 2021 Sep 8;109754.
doi: 10.1016/j.celrep.2021.109754. Online ahead of print.
A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease
Stephanie Patchett[SUP] 1 [/SUP], Zongyang Lv[SUP] 2 [/SUP], Wioletta Rut[SUP] 3 [/SUP], Miklos Békés[SUP] 1 [/SUP], Marcin Drag[SUP] 3 [/SUP], Shaun K Olsen[SUP] 4 [/SUP], Tony T Huang[SUP] 5 [/SUP]
Affiliations
- PMID: 34547223
- DOI: 10.1016/j.celrep.2021.109754
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: COVID-19; DUB; ISG15; K48-linked Ub; PLpro; SARS-CoV-1; SARS-CoV-2; coronavirus; cysteine protease; deubiquitinase; papain-like protease; ubiquitin.