Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin 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 uncovered differential binding stabilities of the two UBL/Ub domains. 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.
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The categories of this paper are: developmental
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The categories of this paper are: genomics
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The categories of this paper are: biology
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The categories of this paper are: toxicology
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The categories of this paper are: scientific
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The categories of this paper are: cell
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The categories of this paper are: neuroscience
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The categories of this paper are: immunology
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The categories of this paper are: microbiology
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The categories of this paper are: systems
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The categories of this paper are: behavior
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The categories of this paper are: plant
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The categories of this paper are: communication
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The categories of this paper are: animal
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The categories of this paper are: pathology
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The categories of this paper are: cancer