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 Laboratory (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. doi: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 = {Sun May 01 00:00:00 EDT 2016},
month = {Sun May 01 00:00:00 EDT 2016}
}
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Works referenced in this record:
Structure and recognition of polyubiquitin chains of different lengths and linkage
journal, December 2011
- Fushman, David; Wilkinson, Keith D.
- F1000 Biology Reports, Vol. 3
Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease
journal, October 2007
- Lindner, Holger A.; Lytvyn, Viktoria; Qi, Hongtao
- Archives of Biochemistry and Biophysics, Vol. 466, Issue 1
Mechanisms Underlying Ubiquitination
journal, June 2001
- Pickart, Cecile M.
- Annual Review of Biochemistry, Vol. 70, Issue 1
SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon
journal, June 2012
- Totura, Allison L.; Baric, Ralph S.
- Current Opinion in Virology, Vol. 2, Issue 3
Regulation and Cellular Roles of Ubiquitin-Specific Deubiquitinating Enzymes
journal, June 2009
- Reyes-Turcu, Francisca E.; Ventii, Karen H.; Wilkinson, Keith D.
- Annual Review of Biochemistry, Vol. 78, Issue 1
Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
journal, October 2014
- Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice
- Nature, Vol. 517, Issue 7532
Ubiquitin chain conformation regulates recognition and activity of interacting proteins
journal, December 2012
- Ye, Yu; Blaser, Georg; Horrocks, Mathew H.
- Nature, Vol. 492, Issue 7428
Structural Analysis of a Viral Ovarian Tumor Domain Protease from the Crimean-Congo Hemorrhagic Fever Virus in Complex with Covalently Bonded Ubiquitin
journal, January 2011
- Capodagli, G. C.; McKercher, M. A.; Baker, E. A.
- Journal of Virology, Vol. 85, Issue 7
Nidovirus papain-like proteases: Multifunctional enzymes with protease, deubiquitinating and deISGylating activities
journal, December 2014
- Mielech, Anna M.; Chen, Yafang; Mesecar, Andrew D.
- Virus Research, Vol. 194
Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease
journal, May 2014
- Ratia, Kiira; Kilianski, Andrew; Baez-Santos, Yahira M.
- PLoS Pathogens, Vol. 10, Issue 5
Mapping the active site of papain with the aid of peptide substrates and inhibitors
journal, February 1970
- Berger, A.; Schechter, I.
- Philosophical Transactions of the Royal Society of London. B, Biological Sciences, Vol. 257, Issue 813, p. 249-264
IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding
journal, April 2009
- Cer, R. Z.; Mudunuri, U.; Stephens, R.
- Nucleic Acids Research, Vol. 37, Issue Web Server
OTU Deubiquitinases Reveal Mechanisms of Linkage Specificity and Enable Ubiquitin Chain Restriction Analysis
journal, July 2013
- Mevissen, Tycho E. T.; Hospenthal, Manuela K.; Geurink, Paul P.
- Cell, Vol. 154, Issue 1
Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2).
journal, August 1992
- Cook, W. J.; Jeffrey, L. C.; Carson, M.
- Journal of Biological Chemistry, Vol. 267, Issue 23
A Native Chemical Ligation Handle that Enables the Synthesis of Advanced Activity-Based Probes: Diubiquitin as a Case Study
journal, March 2014
- Mulder, Monique P. C.; El Oualid, Farid; ter Beek, Jarno
- ChemBioChem, Vol. 15, Issue 7
Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains
journal, August 2008
- Sato, Yusuke; Yoshikawa, Azusa; Yamagata, Atsushi
- Nature, Vol. 455, Issue 7211
Mycobacterial Disease and Impaired IFN- Immunity in Humans with Inherited ISG15 Deficiency
journal, August 2012
- Bogunovic, D.; Byun, M.; Durfee, L. A.
- Science, Vol. 337, Issue 6102
Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme
journal, March 2006
- Ratia, K.; Saikatendu, K. S.; Santarsiero, B. D.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 15
Catalytic Function and Substrate Specificity of the Papain-Like Protease Domain of nsp3 from the Middle East Respiratory Syndrome Coronavirus
journal, August 2014
- Baez-Santos, Y. M.; Mielech, A. M.; Deng, X.
- Journal of Virology, Vol. 88, Issue 21
Specific and Covalent Targeting of Conjugating and Deconjugating Enzymes of Ubiquitin-Like Proteins
journal, January 2004
- Hemelaar, Joris; Borodovsky, Anna; Kessler, Benedikt M.
- Molecular and Cellular Biology, Vol. 24, Issue 1
Governance of Endocytic Trafficking and Signaling by Reversible Ubiquitylation
journal, September 2012
- Clague, Michael J.; Liu, Han; Urbé, Sylvie
- Developmental Cell, Vol. 23, Issue 3
Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology
journal, June 2006
- Kirkpatrick, Donald S.; Hathaway, Nathaniel A.; Hanna, John
- Nature Cell Biology, Vol. 8, Issue 7
Molecular discrimination of structurally equivalent Lys 63‐linked and linear polyubiquitin chains
journal, April 2009
- Komander, David; Reyes‐Turcu, Francisca; Licchesi, Julien D. F.
- EMBO reports, Vol. 10, Issue 5
Ubiquitylation in innate and adaptive immunity
journal, March 2009
- Bhoj, Vijay G.; Chen, Zhijian J.
- Nature, Vol. 458, Issue 7237
A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein
journal, March 1989
- Chau, V.; Tobias, J.; Bachmair, A.
- Science, Vol. 243, Issue 4898
On Terminal Alkynes That Can React with Active-Site Cysteine Nucleophiles in Proteases
journal, February 2013
- Ekkebus, Reggy; van Kasteren, Sander I.; Kulathu, Yogesh
- Journal of the American Chemical Society, Vol. 135, Issue 8
Crystal Structure of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Papain-like Protease Bound to Ubiquitin Facilitates Targeted Disruption of Deubiquitinating Activity to Demonstrate Its Role in Innate Immune Suppression
journal, December 2014
- Bailey-Elkin, Ben A.; Knaap, Robert C. M.; Johnson, Garrett G.
- Journal of Biological Chemistry, Vol. 289, Issue 50
Viral OTU Deubiquitinases: A Structural and Functional Comparison
journal, March 2014
- Bailey-Elkin, Ben A.; van Kasteren, Puck B.; Snijder, Eric J.
- PLoS Pathogens, Vol. 10, Issue 3
Ubiquitination, Ubiquitin-like Modifiers, and Deubiquitination in Viral Infection
journal, June 2009
- Isaacson, Marisa K.; Ploegh, Hidde L.
- Cell Host & Microbe, Vol. 5, Issue 6
Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity
journal, February 2015
- Sato, Yusuke; Goto, Eiji; Shibata, Yuri
- Nature Structural & Molecular Biology, Vol. 22, Issue 3
SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme
journal, May 2015
- Békés, Miklós; Rut, Wioletta; Kasperkiewicz, Paulina
- Biochemical Journal, Vol. 468, Issue 2
Crystal Structure of the Interferon-induced Ubiquitin-like Protein ISG15
journal, May 2005
- Narasimhan, Jana; Wang, Ming; Fu, Zhuji
- Journal of Biological Chemistry, Vol. 280, Issue 29
Non-hydrolyzable Diubiquitin Probes Reveal Linkage-Specific Reactivity of Deubiquitylating Enzymes Mediated by S2 Pockets
journal, April 2016
- Flierman, Dennis; van der Heden van Noort, Gerbrand J.; Ekkebus, Reggy
- Cell Chemical Biology, Vol. 23, Issue 4
OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin
journal, June 2013
- Keusekotten, Kirstin; Elliott, Paul Ronald; Glockner, Laura
- Cell, Vol. 153, Issue 6
The Ubiquitin Code
journal, July 2012
- Komander, David; Rape, Michael
- Annual Review of Biochemistry, Vol. 81, Issue 1
Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice
journal, February 2016
- Channappanavar, Rudragouda; Fehr, Anthony R.; Vijay, Rahul
- Cell Host & Microbe, Vol. 19, Issue 2
Chemical Synthesis of Ubiquitin, Ubiquitin-Based Probes, and Diubiquitin
journal, November 2010
- El Oualid, Farid; Merkx, Remco; Ekkebus, Reggy
- Angewandte Chemie International Edition, Vol. 49, Issue 52