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Article ; Online: In Vitro Insemination of the Microphallid Digenean Gynaecotyla adunca.

Daczkowski, Courtney M / Pung, Oscar J

2016 Volume 102, Issue 1, Page(s) 5–10

Abstract: In vitro cultivation of adult digeneans can benefit research on their biology and contribute to the development of new drugs and vaccines. Successful in vitro growth of excysted metacercariae into adults capable of producing embryonated eggs typically ... ...

Abstract	In vitro cultivation of adult digeneans can benefit research on their biology and contribute to the development of new drugs and vaccines. Successful in vitro growth of excysted metacercariae into adults capable of producing embryonated eggs typically requires that the worms be inseminated. The goal of the study was to develop an in vitro insemination procedure for the progenetic microphallid digenean Gynaecotyla adunca. To do so, we determined the length of time needed for in vitro sperm development in excysted metacercariae and whether the adult worms could self-inseminate in the absence of conspecifics. We also examined the effect of different culture vessels, worm densities, incubation temperatures, length of time incubated with conspecifics, and different pH levels on the percentage of worms inseminated. We found that sperm maturation time for G. adunca was 8-10 hr postexcystment. In the absence of conspecifics, the parasite did not self-inseminate. We observed the highest percentage of inseminated worms when 50 excysted metacercariae were incubated at 37 C for 48 hr in 15-ml conical-bottom tubes containing pH 7 Hank's balanced salt solution. Furthermore, freshly excysted worms incubated in these conditions and then transferred to culture in Dulbecco's modified Eagle medium/F-12 medium and horse serum deposited normal-shaped, embryonated eggs. Our findings provide the basis for a straightforward, reproducible procedure that permits the in vitro insemination of the parasite G. adunca and should be applicable to other progenetic digeneans.
MeSH term(s)	Animals ; Brachyura/parasitology ; Georgia ; Hydrogen-Ion Concentration ; Insemination, Artificial ; Saline Waters ; Sperm Maturation ; Temperature ; Time Factors ; Trematoda/growth & development ; Trematoda/physiology ; Wetlands
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	300870-8
ISSN	1937-2345 ; 0022-3395
ISSN (online)	1937-2345
ISSN	0022-3395
DOI	10.1645/15-805
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Article ; Online: Insights into the Porcine Reproductive and Respiratory Syndrome Virus Viral Ovarian Tumor Domain Protease Specificity for Ubiquitin and Interferon Stimulated Gene Product 15.

Bester, Stephanie M / Daczkowski, Courtney M / Faaberg, Kay S / Pegan, Scott D

ACS infectious diseases

2018 Volume 4, Issue 9, Page(s) 1316–1326

Abstract: Porcine reproductive and respiratory syndrome (PRRS) is a widespread economically devastating disease caused by PRRS virus (PRRSV). First recognized in the late 1980s, PRRSV is known to undergo somatic mutations and high frequency viral recombination, ... ...

Abstract	Porcine reproductive and respiratory syndrome (PRRS) is a widespread economically devastating disease caused by PRRS virus (PRRSV). First recognized in the late 1980s, PRRSV is known to undergo somatic mutations and high frequency viral recombination, which leads to many diverse viral strains. This includes differences within viral virulence factors, such as the viral ovarian tumor domain (vOTU) protease, also referred to as the papain-like protease 2. These proteases down-regulate innate immunity by deubiquitinating proteins targeted by the cell for further processing and potentially also acting against interferon-stimulated genes (ISGs). Recently, vOTUs from vaccine derivative Ingelvac PRRS modified live virus (MLV) and the highly pathogenic PRRSV strain JXwn06 were biochemically characterized, revealing a marked difference in activity toward K63 linked polyubiquitin chains and a limited preference for interferon-stimulated gene product 15 (ISG15) substrates. To extend our research, the vOTUs from NADC31 (low virulence) and SDSU73 (moderately virulent) were biochemically characterized using a myriad of ubiquitin and ISG15 related assays. The K63 polyubiquitin cleavage activity profiles of these vOTUs were found to track with the established pathogenesis of MLV, NADC31, SDSU73, and JXwn06 strains. Fascinatingly, NADC31 demonstrated significantly enhanced activity toward ISG15 substrates compared to its counterparts. Utilizing this information and strain-strain differences within the vOTU encoding region, sites were identified that can modulate K63 polyubiquitin and ISG15 cleavage activities. This information represents the basis for new tools to probe the role of vOTUs in the context of PRRSV pathogenesis.
MeSH term(s)	Amino Acid Sequence ; Animals ; Interferon Regulatory Factors/chemistry ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/genetics ; Peptide Hydrolases/metabolism ; Polyubiquitin/chemistry ; Polyubiquitin/genetics ; Polyubiquitin/metabolism ; Porcine Reproductive and Respiratory Syndrome/genetics ; Porcine Reproductive and Respiratory Syndrome/metabolism ; Porcine Reproductive and Respiratory Syndrome/virology ; Porcine respiratory and reproductive syndrome virus/chemistry ; Porcine respiratory and reproductive syndrome virus/enzymology ; Porcine respiratory and reproductive syndrome virus/genetics ; Porcine respiratory and reproductive syndrome virus/pathogenicity ; Sequence Alignment ; Swine ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virulence
Chemical Substances	Interferon Regulatory Factors ; Viral Proteins ; Polyubiquitin (120904-94-1) ; Peptide Hydrolases (EC 3.4.-)
Keywords	covid19
Language	English
Publishing date	2018-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.8b00068
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Article ; Online: Structural insights into the interaction of papain-like protease 2 from the alphacoronavirus porcine epidemic diarrhea virus and ubiquitin.

Durie, Ian A / Dzimianski, John V / Daczkowski, Courtney M / McGuire, Jack / Faaberg, Kay / Pegan, Scott D

Acta crystallographica. Section D, Structural biology

2021 Volume 77, Issue Pt 7, Page(s) 943–953

Abstract: Porcine epidemic diarrhea is a devastating porcine disease that is caused by the alphacoronavirus porcine epidemic diarrhea virus (PEDV). Like other members of the Coronaviridae family, PEDV encodes a multifunctional papain-like protease 2 (PLP2) that ... ...

Abstract	Porcine epidemic diarrhea is a devastating porcine disease that is caused by the alphacoronavirus porcine epidemic diarrhea virus (PEDV). Like other members of the Coronaviridae family, PEDV encodes a multifunctional papain-like protease 2 (PLP2) that has the ability to process the coronavirus viral polyprotein to aid in RNA replication and antagonize the host innate immune response through cleavage of the regulatory proteins ubiquitin (Ub) and/or interferon-stimulated gene product 15 (ISG15) (deubiquitination and deISGylation, respectively). Because Betacoronavirus PLPs have been well characterized, it was sought to determine how PLP2 from the alphacoronavirus PEDV differentiates itself from its related counterparts. PEDV PLP2 was first biochemically characterized, and a 3.1 Å resolution crystal structure of PEDV PLP2 bound to Ub was then solved, providing insight into how Alphacoronavirus PLPs bind to their preferred substrate, Ub. It was found that PEDV PLP2 is a deubiquitinase and readily processes a variety of di-Ub linkages, in comparison with its Betacoronavirus counterparts, which have a narrower range of di-Ub activity but process both Ub and ISG15.
MeSH term(s)	Animals ; Coronavirus Infections/virology ; Coronavirus Papain-Like Proteases/chemistry ; Coronavirus Papain-Like Proteases/metabolism ; Crystallography, X-Ray ; Porcine epidemic diarrhea virus/physiology ; Protein Binding ; Protein Conformation ; Swine ; Ubiquitin/metabolism
Chemical Substances	Ubiquitin ; Coronavirus Papain-Like Proteases (EC 3.4.22.2)
Language	English
Publishing date	2021-06-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S205979832100509X
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Article ; Online: Structural Basis for the Inhibition of CRISPR-Cas12a by Anti-CRISPR Proteins.

Zhang, Heng / Li, Zhuang / Daczkowski, Courtney M / Gabel, Clinton / Mesecar, Andrew D / Chang, Leifu

Cell host & microbe

2019 Volume 25, Issue 6, Page(s) 815–826.e4

Abstract: CRISPR-Cas12a (Cpf1), a type V CRISPR-associated nuclease, provides bacterial immunity against bacteriophages and plasmids but also serves as a tool for genome editing. Foreign nucleic acids are integrated into the CRISPR locus, prompting transcription ... ...

Abstract	CRISPR-Cas12a (Cpf1), a type V CRISPR-associated nuclease, provides bacterial immunity against bacteriophages and plasmids but also serves as a tool for genome editing. Foreign nucleic acids are integrated into the CRISPR locus, prompting transcription of CRISPR RNAs (crRNAs) that guide Cas12a cleavage of foreign complementary DNA. However, mobile genetic elements counteract Cas12a with inhibitors, notably type V-A anti-CRISPRs (AcrVAs). We present cryoelectron microscopy structures of Cas12a-crRNA bound to AcrVA1 and AcrVA4 at 3.5 and 3.3 Å resolutions, respectively. AcrVA1 is sandwiched between the recognition (REC) and nuclease (NUC) lobes of Cas12a and inserts into the binding pocket for the protospacer-adjacent motif (PAM), a short DNA sequence guiding Cas12a targeting. AcrVA1 cleaves crRNA in a Cas12a-dependent manner, inactivating Cas12a-crRNA complexes. The AcrVA4 dimer is anchored around the crRNA pseudoknot of Cas12a-crRNA, preventing required conformational changes for crRNA-DNA heteroduplex formation. These results uncover molecular mechanisms for CRISPR-Cas12a inhibition, providing insights into bacteria-phage dynamics.
MeSH term(s)	CRISPR-Cas Systems ; Cryoelectron Microscopy ; Endodeoxyribonucleases/antagonists & inhibitors ; Endodeoxyribonucleases/metabolism ; Endodeoxyribonucleases/ultrastructure ; Enzyme Inhibitors/metabolism ; Protein Binding ; Protein Conformation ; RNA, Guide, CRISPR-Cas Systems/metabolism ; RNA, Guide, CRISPR-Cas Systems/ultrastructure ; Ribonucleases/metabolism ; Ribonucleases/ultrastructure
Chemical Substances	Enzyme Inhibitors ; RNA, Guide, CRISPR-Cas Systems ; Endodeoxyribonucleases (EC 3.1.-) ; Ribonucleases (EC 3.1.-)
Language	English
Publishing date	2019-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2019.05.004
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Article ; Online: 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.

Langley, Caroline / Goodwin, Octavia / Dzimianski, John V / Daczkowski, Courtney M / Pegan, Scott D

Acta crystallographica. Section D, Structural biology

2019 Volume 75, Issue Pt 1, Page(s) 21–31

Abstract: Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin- ... ...

Abstract	Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species-species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species-species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15-protein engagements was illuminated.
MeSH term(s)	Animals ; Chiroptera ; Crystallography, X-Ray ; Cytokines/immunology ; Humans ; Interferons/immunology ; Mice ; Protein Domains ; Protein Processing, Post-Translational ; Ubiquitins/chemistry ; Viral Proteins/metabolism
Chemical Substances	Cytokines ; G1p2 protein, mouse ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; Interferons (9008-11-1)
Keywords	covid19
Language	English
Publishing date	2019-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798318015322
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Article ; Online: Engineering the Organophosphorus Acid Anhydrolase Enzyme for Increased Catalytic Efficiency and Broadened Stereospecificity on Russian VX.

Daczkowski, Courtney M / Pegan, Scott D / Harvey, Steven P

Biochemistry

2015 Volume 54, Issue 41, Page(s) 6423–6433

Abstract: The enzyme organophosphorus acid anhydrolase (OPAA), from Alteromonas sp. JD6.5, has been shown to rapidly catalyze the hydrolysis of a number of toxic organophosphorus compounds, including several G-type chemical nerve agents. The enzyme was cloned into ...

Abstract	The enzyme organophosphorus acid anhydrolase (OPAA), from Alteromonas sp. JD6.5, has been shown to rapidly catalyze the hydrolysis of a number of toxic organophosphorus compounds, including several G-type chemical nerve agents. The enzyme was cloned into Escherichia coli and can be produced up to approximately 50% of cellular protein. There have been no previous reports of OPAA activity on VR {Russian VX, O-isobutyl S-[2-(diethylamino)ethyl] methylphosphonothioate}, and our studies reported here show that wild-type OPAA has poor catalytic efficacy toward VR. However, via application of a structurally aided protein engineering approach, significant improvements in catalytic efficiency were realized via optimization of the small pocket within the OPAA's substrate-binding site. This optimization involved alterations at only three amino acid sites resulting in a 30-fold increase in catalytic efficiency toward racemic VR, with a strong stereospecificity toward the P(+) enantiomer. X-ray structures of this mutant as well as one of its predecessors provide potential structural rationales for their effect on the OPAA active site. Additionally, a fourth mutation at a site near the small pocket was found to relax the stereospecificity of the OPAA enzyme. Thus, it allows the altered enzyme to effectively process both VR enantiomers and should be a useful genetic background in which to seek further improvements in OPAA VR activity.
MeSH term(s)	Alteromonas/chemistry ; Alteromonas/enzymology ; Alteromonas/genetics ; Alteromonas/metabolism ; Aryldialkylphosphatase/chemistry ; Aryldialkylphosphatase/genetics ; Aryldialkylphosphatase/metabolism ; Catalytic Domain ; Cloning, Molecular ; Crystallography, X-Ray ; Escherichia coli/genetics ; Hydrolysis ; Models, Molecular ; Mutagenesis, Site-Directed ; Organothiophosphorus Compounds/metabolism ; Protein Conformation ; Protein Engineering ; Stereoisomerism ; Substrate Specificity
Chemical Substances	Organothiophosphorus Compounds ; Aryldialkylphosphatase (EC 3.1.8.1) ; S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate (LG34LSI9IU)
Language	English
Publishing date	2015-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.5b00624
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Article ; Online: Mn

Minasov, George / Rosas-Lemus, Monica / Shuvalova, Ludmilla / Inniss, Nicole L / Brunzelle, Joseph S / Daczkowski, Courtney M / Hoover, Paul / Mesecar, Andrew D / Satchell, Karla J F

Science signaling

2021 Volume 14, Issue 689

Abstract: Capping of viral messenger RNAs is essential for efficient translation, for virus replication, and for preventing detection by the host cell innate response system. The SARS-CoV-2 genome encodes the 2'- ...

Abstract	Capping of viral messenger RNAs is essential for efficient translation, for virus replication, and for preventing detection by the host cell innate response system. The SARS-CoV-2 genome encodes the 2'-
MeSH term(s)	Amino Acid Sequence ; COVID-19/virology ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Manganese/metabolism ; Methylation ; Methyltransferases/chemistry ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Models, Molecular ; Nucleic Acid Conformation ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA Caps/metabolism ; RNA Stability ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; S-Adenosylmethionine/chemistry ; S-Adenosylmethionine/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Signal Transduction ; Substrate Specificity ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	NSP16 protein, SARS-CoV-2 ; RNA Caps ; RNA, Messenger ; RNA, Viral ; Recombinant Proteins ; Viral Nonstructural Proteins ; Manganese (42Z2K6ZL8P) ; S-Adenosylmethionine (7LP2MPO46S) ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2021-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abh2071
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Article ; Online: Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity.

Dzimianski, John V / Beldon, Brianna S / Daczkowski, Courtney M / Goodwin, Octavia Y / Scholte, Florine E M / Bergeron, Éric / Pegan, Scott D

PLoS pathogens

2019 Volume 15, Issue 1, Page(s) e1007515

Abstract: Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain ... ...

Abstract	Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain proteases possessing deubiquitinase (DUB) and/or deISGylase functions. This includes viruses in the Nairoviridae family that encode a viral homologue of the ovarian tumor protease (vOTU). vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins. There are currently about 40 known nairoviruses classified into fourteen species. Recent genomic characterization has revealed a high degree of diversity, with vOTUs showing less than 25% amino acids identities within the family. Previous investigations have been limited to only a few closely related nairoviruses, leaving it unclear what impact this diversity has on vOTU function. To probe the effects of vOTU diversity on enzyme activity and specificity, we assessed representative vOTUs spanning the Nairoviridae family towards Ub and ISG15 fluorogenic substrates. This revealed great variation in enzymatic activity and specific substrate preferences. A subset of the vOTUs were further assayed against eight biologically relevant di-Ub substrates, uncovering both common trends and distinct preferences of poly-Ub linkages by vOTUs. Four novel X-ray crystal structures were obtained that provide a biochemical rationale for vOTU substrate preferences and elucidate structural features that distinguish the vOTUs, including a motif in the Hughes orthonairovirus species that has not been previously observed in OTU domains. Additionally, structure-informed mutagenesis provided the first direct evidence of a second site involved in di-Ub binding for vOTUs. These results provide new insight into nairovirus evolution and pathogenesis, and further enhances the development of tools for therapeutic purposes.
MeSH term(s)	Crystallography, X-Ray/methods ; Deubiquitinating Enzymes/metabolism ; Female ; Genetic Variation/genetics ; Genomics ; Humans ; Nairovirus/genetics ; Nairovirus/pathogenicity ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/virology ; Ovary/metabolism ; Peptide Hydrolases/genetics ; Peptide Hydrolases/metabolism ; Phylogeny ; Protein Binding ; Protein Domains ; Protein Processing, Post-Translational/genetics ; Proteolysis ; Sequence Homology, Amino Acid ; Ubiquitin/metabolism ; Ubiquitination/genetics ; Ubiquitins/metabolism ; Viral Proteins/metabolism
Chemical Substances	Ubiquitin ; Ubiquitins ; Viral Proteins ; Peptide Hydrolases (EC 3.4.-) ; Deubiquitinating Enzymes (EC 3.4.19.12)
Keywords	covid19
Language	English
Publishing date	2019-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1007515
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Article ; Online: Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus.

Daczkowski, Courtney M / Goodwin, Octavia Y / Dzimianski, John V / Farhat, Jonathan J / Pegan, Scott D

Journal of virology

2017 Volume 91, Issue 23

Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV ... ...

Abstract	Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant ongoing threat to global human health. As part of its viral genome, MERS-CoV encodes a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize type I interferon (IFN-I) immune pathways. This activity is in addition to its viral polypeptide cleavage function. Although the overall impact of MERS-CoV PLpro function is observed to be essential, difficulty has been encountered in delineating the importance of its separate functions, particularly its deISGylase activity. As a result, the interface of MERS-CoV and human interferon-stimulated gene product 15 (hISG15) was probed with isothermal calorimetry, which suggests that the C-terminal domain of hISG15 is principally responsible for interactions. Subsequently, the structure of MERS-CoV PLpro was solved to 2.4 Å in complex with the C-terminal domain of hISG15. Utilizing this structural information, mutants were generated that lacked appreciable deISGylase activity but retained wild-type deubiquitinase and peptide cleavage activities. Hence, this provides a new platform for understanding viral deISGylase activity within MERS-CoV and other CoVs.
MeSH term(s)	Calorimetry ; Crystallography, X-Ray ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Cytokines/chemistry ; Cytokines/metabolism ; Deubiquitinating Enzymes/metabolism ; Host-Pathogen Interactions ; Humans ; Interferons/antagonists & inhibitors ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Middle East Respiratory Syndrome Coronavirus/genetics ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Middle East Respiratory Syndrome Coronavirus/pathogenicity ; Mutation ; Ubiquitin/metabolism ; Ubiquitins/chemistry ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/metabolism
Chemical Substances	Cytokines ; Ubiquitin ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; Interferons (9008-11-1) ; Deubiquitinating Enzymes (EC 3.4.19.12) ; 3C-like proteinase, Coronavirus (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-)
Keywords	covid19
Language	English
Publishing date	2017-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01067-17
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Article: Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species

Daczkowski, Courtney M / Clasman, Jozlyn R / Dzimianski, John V / Goodwin, Octavia / Mesecar, Andrew D / Pegan, Scott D

Journal of Molecular Biology. 2017,

2017

Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronaviruses encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and ... ...

Abstract	Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronaviruses 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 coronaviral PLP at the structural and biochemical levels are poorly understood. Therefore, the activity of PLPs from SARS-CoV, Middle East respiratory syndrome coronavirus, 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 PLP in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). 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.
Keywords	eukaryotic cells ; genes ; humans ; innate immunity ; mice ; Middle East respiratory syndrome coronavirus ; Murine hepatitis virus ; polyproteins ; post-translational modification ; proteinases ; RNA replication ; Severe acute respiratory syndrome coronavirus ; thermodynamics ; ubiquitin ; X-radiation ; Middle East ; covid19
Language	English
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2017.04.011
Database	NAL-Catalogue (AGRICOLA)

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