@article{f9d098589cc64c4fb570a0765c60b0b9,
title = "A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease",
abstract = "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.",
keywords = "COVID-19, DUB, ISG15, K48-linked Ub, PLpro, SARS-CoV-1, SARS-CoV-2, coronavirus, cysteine protease, deubiquitinase, papain-like protease, ubiquitin",
author = "Stephanie Patchett and Zongyang Lv and Wioletta Rut and Miklos B{\'e}k{\'e}s and Marcin Drag and Olsen, {Shaun K.} and Huang, {Tony T.}",
note = "Funding Information: This work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the NIH ( P30 GM124165 ). The Eiger 16M detector on the 24-ID-E beam line is funded by a NIH-ORIP HEI grant ( S10OD021527 ). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357 . This work is based on research conducted in the Structural Biology Core Facilities-X-ray Crystallography Core Laboratory, a part of the Institutional Research Cores at the University of Texas Health Science Center at San Antonio supported by the Office of the Vice President for Research and the Mays Cancer Center Drug Discovery and Structural Biology Shared Resource ( NIH P30 CA054174 ). Research reported in this publication was supported by CPRIT RR200030 and NIH grants R01 GM115568 and R01 GM128731 (to S.K.O.) and R01 ES025166 and R35 GM139610 (to T.T.H.). S.P. is an American Cancer Society Postdoctoral Fellow ( PF-18-235-01-RMC ). This project was supported by the National Science Center grant 2015/17/N/ST5/03072 (Preludium 9 ) in Poland (to W.R.), UMO-2020/01/0/NZ1/00063 (to M.D.), and the “TEAM/2017-4/32” project, which is carried out within the TEAM program of the Foundation for Polish Science, cofinanced by the European Union under the European Regional Development Fund (to M.D.). Funding Information: This work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the NIH (P30 GM124165). The Eiger 16M detector on the 24-ID-E beam line is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This work is based on research conducted in the Structural Biology Core Facilities-X-ray Crystallography Core Laboratory, a part of the Institutional Research Cores at the University of Texas Health Science Center at San Antonio supported by the Office of the Vice President for Research and the Mays Cancer Center Drug Discovery and Structural Biology Shared Resource (NIH P30 CA054174). Research reported in this publication was supported by CPRIT RR200030 and NIH grants R01 GM115568 and R01 GM128731 (to S.K.O.) and R01 ES025166 and R35 GM139610 (to T.T.H.). S.P. is an American Cancer Society Postdoctoral Fellow (PF-18-235-01-RMC). This project was supported by the National Science Center grant 2015/17/N/ST5/03072 (Preludium 9) in Poland (to W.R.), UMO-2020/01/0/NZ1/00063 (to M.D.), and the ?TEAM/2017-4/32? project, which is carried out within the TEAM program of the Foundation for Polish Science, cofinanced by the European Union under the European Regional Development Fund (to M.D.). Conceptualization, S.P. Z.L. S.K.O. and T.T.H.; methodology, S.P. Z.L. S.K.O. and T.T.H.; investigation, S.P. Z.L. and W.R.; resources, S.P. Z.L. W.R. M.B. and M.D.; formal analysis, S.P. Z.L. S.K.O. and T.T.H.; visualization, S.P. and Z.L.; writing ? original draft, S.P.; writing ? review & editing, S.P. Z.L. W.R. M.B. M.D. S.K.O. and T.T.H. 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. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "28",
doi = "10.1016/j.celrep.2021.109754",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}