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Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species

Journal Article · · Journal of Molecular Biology
 [1];  [1];  [2];  [1];  [2];  [1]
  1. Univ. of Georgia, Athens, GA (United States)
  2. Purdue Univ., West Lafayette, IN (United States)
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Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS–CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic, and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronavirus PLP’s interface with ISG15 via SARS-CoV PLpro in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). Here, the first X-ray structure of the full-length mISG15 protein is also reported and highlights a unique, twisted hinge region of ISG15 that is not conserved in hISG15, suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities among coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
NIH/NIAID; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1368288
Alternate ID(s):
OSTI ID: 1415315
Journal Information:
Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 11 Vol. 429; ISSN 0022-2836
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (15)

Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease journal February 2020
ISG15: It's Complicated journal October 2019
ISG15 in antiviral immunity and beyond journal May 2018
The current landscape of coronavirus-host protein–protein interactions journal August 2020
Determining the molecular drivers of species-specific interferon-stimulated gene product 15 interactions with nairovirus ovarian tumor domain proteases journal December 2019
The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species journal September 2018
Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity journal January 2019
Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling text January 2022
Analysis of Whole Genome Sequences and Homology Modelling of a 3C Like Peptidase and a Non-Structural Protein of the Novel Coronavirus COVID-19 Shows Protein Ligand Interaction with an Aza-Peptide and a Noncovalent Lead Inhibitor with Possible Antiviral Properties preprint February 2020
COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms journal March 2021
Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19 journal May 2020
USP18 – a multifunctional component in the interferon response journal November 2018
Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement journal January 2019
ISGylation – a key to lock the cell gates for preventing the spread of threats journal August 2017
The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species. text January 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ISG15
Middle East respiratory syndrome
coronavirus
severe acute respiratory syndrome
ubiquitin