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Title: Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease

Abstract

Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUbLys48 products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUbLys48 activity-based probe. SARS PLpro binds diUbLys48 in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUbLys48 chains is predicated on contacts in the S2 site and enhanced by an S1-S1' preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUbLys48 specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Inst. of General Medical Sciences (NIGMS); National Cancer Inst.; NYU Laura & Isaac Perlmutter Cancer Center Support Grant’s Developmental Project Program; NWO-VENI
OSTI Identifier:
1357829
Alternate Identifier(s):
OSTI ID: 1256348; OSTI ID: 1326434
Grant/Contract Number:  
AC02-06CH11357; P41 GM103403; F32GM100598; GM084244; ES025166; GM065872; P30 CA008748; P30 CA016087; 722.014.002; 281699
Resource Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Name: Molecular Cell Journal Volume: 62 Journal Issue: 4; Journal ID: ISSN 1097-2765
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Békés, Miklós, van der Heden van Noort, Gerbrand J., Ekkebus, Reggy, Ovaa, Huib, Huang, Tony T., and Lima, Christopher D. Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease. United States: N. p., 2016. Web. https://doi.org/10.1016/j.molcel.2016.04.016.
Békés, Miklós, van der Heden van Noort, Gerbrand J., Ekkebus, Reggy, Ovaa, Huib, Huang, Tony T., & Lima, Christopher D. Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease. United States. https://doi.org/10.1016/j.molcel.2016.04.016
Békés, Miklós, van der Heden van Noort, Gerbrand J., Ekkebus, Reggy, Ovaa, Huib, Huang, Tony T., and Lima, Christopher D. Sun . "Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease". United States. https://doi.org/10.1016/j.molcel.2016.04.016.
@article{osti_1357829,
title = {Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease},
author = {Békés, Miklós and van der Heden van Noort, Gerbrand J. and Ekkebus, Reggy and Ovaa, Huib and Huang, Tony T. and Lima, Christopher D.},
abstractNote = {Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUbLys48 products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUbLys48 activity-based probe. SARS PLpro binds diUbLys48 in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUbLys48 chains is predicated on contacts in the S2 site and enhanced by an S1-S1' preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUbLys48 specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections.},
doi = {10.1016/j.molcel.2016.04.016},
journal = {Molecular Cell},
number = 4,
volume = 62,
place = {United States},
year = {2016},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.molcel.2016.04.016

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Cited by: 11 works
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