A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.
Amino Acid Sequence
/ genetics
Binding Sites
/ genetics
COVID-19
/ genetics
Coronavirus Papain-Like Proteases
/ genetics
HEK293 Cells
Humans
Papain
/ chemistry
Peptide Hydrolases
/ chemistry
Protein Binding
/ genetics
SARS-CoV-2
/ genetics
Substrate Specificity
/ genetics
Ubiquitin
/ metabolism
Ubiquitins
/ metabolism
Viral Proteins
/ metabolism
COVID-19
DUB
ISG15
K48-linked Ub
PLpro
SARS-CoV-1
SARS-CoV-2
coronavirus
cysteine protease
deubiquitinase
papain-like protease
ubiquitin
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
28 09 2021
28 09 2021
Historique:
received:
26
02
2021
revised:
15
07
2021
accepted:
02
09
2021
pubmed:
22
9
2021
medline:
13
10
2021
entrez:
21
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34547223
pii: S2211-1247(21)01208-0
doi: 10.1016/j.celrep.2021.109754
pmc: PMC8423903
pii:
doi:
Substances chimiques
Ubiquitin
0
Ubiquitins
0
Viral Proteins
0
Peptide Hydrolases
EC 3.4.-
Coronavirus Papain-Like Proteases
EC 3.4.22.2
Papain
EC 3.4.22.2
papain-like protease, SARS-CoV-2
EC 3.4.22.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109754Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM139610
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM128731
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA054174
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES025166
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM115568
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests M.B. is an employee of Arvinas, Inc, which was not involved in this study. T.T.H. is a member of the advisory board for Cell Reports. The remaining authors declare no competing interests.
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