Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin.

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-Ub ₂ ) with nanomolar affinity and detect alternate weaker-binding modes. Crystal structures of untethered PLpro complexes with ISG15 and K48-Ub ₂ combined with solution NMR and cross-linking mass spectrometry revealed how the two domains of ISG15 or K48-Ub ₂ are differen

SUBMITTER: Wydorski PM 

PROVIDER: S-EPMC9094096 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature