Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin.
Nat Commun
; 14(1): 2366, 2023 04 25.
Article
in English
| MEDLINE | ID: covidwho-2305876
ABSTRACT
The Papain-like protease (PLpro) is a domain of a multi-functional, non-structural protein 3 of coronaviruses. PLpro cleaves viral polyproteins and posttranslational conjugates with poly-ubiquitin and protective ISG15, composed of two ubiquitin-like (UBL) domains. Across coronaviruses, PLpro showed divergent selectivity for recognition and cleavage of posttranslational conjugates despite sequence conservation. We show that SARS-CoV-2 PLpro binds human ISG15 and K48-linked di-ubiquitin (K48-Ub2) with nanomolar affinity and detect alternate weaker-binding modes. Crystal structures of untethered PLpro complexes with ISG15 and K48-Ub2 combined with solution NMR and cross-linking mass spectrometry revealed how the two domains of ISG15 or K48-Ub2 are differently utilized in interactions with PLpro. Analysis of protein interface energetics predicted differential binding stabilities of the two UBL/Ub domains that were validated experimentally. We emphasize how substrate recognition can be tuned to cleave specifically ISG15 or K48-Ub2 modifications while retaining capacity to cleave mono-Ub conjugates. These results highlight alternative druggable surfaces that would inhibit PLpro function.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Ubiquitin
/
SARS-CoV-2
/
COVID-19
Type of study:
Prognostic study
/
Randomized controlled trials
Limits:
Humans
Language:
English
Journal:
Nat Commun
Journal subject:
Biology
/
Science
Year:
2023
Document Type:
Article
Affiliation country:
S41467-023-38031-5
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