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

Pawel M. Wydorski, Jerzy Osipiuk, Benjamin T. Lanham, Christine Tesar, Michael Endres, Elizabeth Engle, Robert Jedrzejczak, Vishruth Mullapudi, Karolina Michalska, Krzysztof Fidelis, David Fushman (), Andrzej Joachimiak () and Lukasz A. Joachimiak ()
Additional contact information
Pawel M. Wydorski: University of Texas Southwestern Medical Center
Jerzy Osipiuk: University of Chicago
Benjamin T. Lanham: University of Maryland
Christine Tesar: University of Chicago
Michael Endres: University of Chicago
Elizabeth Engle: University of Maryland
Robert Jedrzejczak: University of Chicago
Vishruth Mullapudi: University of Texas Southwestern Medical Center
Karolina Michalska: University of Chicago
Krzysztof Fidelis: University of California
David Fushman: University of Maryland
Andrzej Joachimiak: University of Chicago
Lukasz A. Joachimiak: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38031-5

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