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.
Identifieur interne : 001815 ( PubMed/Curation ); précédent : 001814; suivant : 001816Crystal 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.
Auteurs : Ben A. Bailey-Elkin [Canada] ; Robert C M. Knaap [Pays-Bas] ; Garrett G. Johnson [Canada] ; Tim J. Dalebout [Pays-Bas] ; Dennis K. Ninaber [Pays-Bas] ; Puck B. Van Kasteren [Pays-Bas] ; Peter J. Bredenbeek [Pays-Bas] ; Eric J. Snijder [Pays-Bas] ; Marjolein Kikkert [Pays-Bas] ; Brian L. Mark [Canada]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2014.
Descripteurs français
- KwdFr :
- Cellules HEK293, Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Cristallographie aux rayons X, Domaine catalytique, Humains, Immunité innée, Modèles moléculaires, Motifs d'acides aminés, Mutagenèse, Mutation, Papaïne (), Papaïne (génétique), Papaïne (métabolisme), Tolérance immunitaire, Ubiquitine (), Ubiquitine (métabolisme), Ubiquitinylation.
- MESH :
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- génétique : Papaïne.
- métabolisme : Papaïne, Ubiquitine.
- Cellules HEK293, Cristallographie aux rayons X, Domaine catalytique, Humains, Immunité innée, Modèles moléculaires, Motifs d'acides aminés, Mutagenèse, Mutation, Papaïne, Tolérance immunitaire, Ubiquitine, Ubiquitinylation.
English descriptors
- KwdEn :
- Amino Acid Motifs, Catalytic Domain, Crystallography, X-Ray, HEK293 Cells, Humans, Immune Tolerance, Immunity, Innate, Middle East Respiratory Syndrome Coronavirus (enzymology), Models, Molecular, Mutagenesis, Mutation, Papain (chemistry), Papain (genetics), Papain (metabolism), Ubiquitin (chemistry), Ubiquitin (metabolism), Ubiquitination.
- MESH :
- chemical , chemistry : Papain, Ubiquitin.
- enzymology : Middle East Respiratory Syndrome Coronavirus.
- chemical , genetics : Papain.
- chemical , metabolism : Papain, Ubiquitin.
- Amino Acid Motifs, Catalytic Domain, Crystallography, X-Ray, HEK293 Cells, Humans, Immune Tolerance, Immunity, Innate, Models, Molecular, Mutagenesis, Mutation, Ubiquitination.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3↓4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-β promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-β promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection.
DOI: 10.1074/jbc.M114.609644
PubMed: 25320088
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Bredenbeek</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. 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Mark</name><affiliation wicri:level="1"><nlm:affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and brian.mark@umanitoba.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:25320088</idno><idno type="pmid">25320088</idno><idno type="doi">10.1074/jbc.M114.609644</idno><idno type="wicri:Area/PubMed/Corpus">001815</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001815</idno><idno type="wicri:Area/PubMed/Curation">001815</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001815</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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.</title><author><name sortKey="Bailey Elkin, Ben A" sort="Bailey Elkin, Ben A" uniqKey="Bailey Elkin B" first="Ben A" last="Bailey-Elkin">Ben A. Bailey-Elkin</name><affiliation wicri:level="1"><nlm:affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and.</nlm:affiliation><country>Canada</country><wicri:regionArea>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2</wicri:regionArea></affiliation></author><author><name sortKey="Knaap, Robert C M" sort="Knaap, Robert C M" uniqKey="Knaap R" first="Robert C M" last="Knaap">Robert C M. Knaap</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Johnson, Garrett G" sort="Johnson, Garrett G" uniqKey="Johnson G" first="Garrett G" last="Johnson">Garrett G. Johnson</name><affiliation wicri:level="1"><nlm:affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and.</nlm:affiliation><country>Canada</country><wicri:regionArea>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2</wicri:regionArea></affiliation></author><author><name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J" last="Dalebout">Tim J. Dalebout</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Ninaber, Dennis K" sort="Ninaber, Dennis K" uniqKey="Ninaber D" first="Dennis K" last="Ninaber">Dennis K. Ninaber</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Van Kasteren, Puck B" sort="Van Kasteren, Puck B" uniqKey="Van Kasteren P" first="Puck B" last="Van Kasteren">Puck B. Van Kasteren</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J" last="Bredenbeek">Peter J. Bredenbeek</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name><affiliation wicri:level="1"><nlm:affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands m.kikkert@lumc.nl.</nlm:affiliation><country wicri:rule="url">Pays-Bas</country><wicri:regionArea>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L" last="Mark">Brian L. Mark</name><affiliation wicri:level="1"><nlm:affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and brian.mark@umanitoba.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2</wicri:regionArea></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Motifs</term><term>Catalytic Domain</term><term>Crystallography, X-Ray</term><term>HEK293 Cells</term><term>Humans</term><term>Immune Tolerance</term><term>Immunity, Innate</term><term>Middle East Respiratory Syndrome Coronavirus (enzymology)</term><term>Models, Molecular</term><term>Mutagenesis</term><term>Mutation</term><term>Papain (chemistry)</term><term>Papain (genetics)</term><term>Papain (metabolism)</term><term>Ubiquitin (chemistry)</term><term>Ubiquitin (metabolism)</term><term>Ubiquitination</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cellules HEK293</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie)</term><term>Cristallographie aux rayons X</term><term>Domaine catalytique</term><term>Humains</term><term>Immunité innée</term><term>Modèles moléculaires</term><term>Motifs d'acides aminés</term><term>Mutagenèse</term><term>Mutation</term><term>Papaïne ()</term><term>Papaïne (génétique)</term><term>Papaïne (métabolisme)</term><term>Tolérance immunitaire</term><term>Ubiquitine ()</term><term>Ubiquitine (métabolisme)</term><term>Ubiquitinylation</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Papain</term><term>Ubiquitin</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Papain</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Papaïne</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Papain</term><term>Ubiquitin</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Papaïne</term><term>Ubiquitine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Motifs</term><term>Catalytic Domain</term><term>Crystallography, X-Ray</term><term>HEK293 Cells</term><term>Humans</term><term>Immune Tolerance</term><term>Immunity, Innate</term><term>Models, Molecular</term><term>Mutagenesis</term><term>Mutation</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cellules HEK293</term><term>Cristallographie aux rayons X</term><term>Domaine catalytique</term><term>Humains</term><term>Immunité innée</term><term>Modèles moléculaires</term><term>Motifs d'acides aminés</term><term>Mutagenèse</term><term>Mutation</term><term>Papaïne</term><term>Tolérance immunitaire</term><term>Ubiquitine</term><term>Ubiquitinylation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3↓4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-β promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-β promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25320088</PMID><DateCompleted><Year>2015</Year><Month>02</Month><Day>12</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>28</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><Volume>289</Volume><Issue>50</Issue><PubDate><Year>2014</Year><Month>Dec</Month><Day>12</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. Chem.</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>34667-82</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M114.609644</ELocationID><Abstract><AbstractText>Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3↓4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-β promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-β promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection. </AbstractText><CopyrightInformation>© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bailey-Elkin</LastName><ForeName>Ben A</ForeName><Initials>BA</Initials><AffiliationInfo><Affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Knaap</LastName><ForeName>Robert C M</ForeName><Initials>RC</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Johnson</LastName><ForeName>Garrett G</ForeName><Initials>GG</Initials><AffiliationInfo><Affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dalebout</LastName><ForeName>Tim J</ForeName><Initials>TJ</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ninaber</LastName><ForeName>Dennis K</ForeName><Initials>DK</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Kasteren</LastName><ForeName>Puck B</ForeName><Initials>PB</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bredenbeek</LastName><ForeName>Peter J</ForeName><Initials>PJ</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Snijder</LastName><ForeName>Eric J</ForeName><Initials>EJ</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kikkert</LastName><ForeName>Marjolein</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>the Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands m.kikkert@lumc.nl.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mark</LastName><ForeName>Brian L</ForeName><Initials>BL</Initials><AffiliationInfo><Affiliation>From the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada and brian.mark@umanitoba.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>4REZ</AccessionNumber><AccessionNumber>4RF0</AccessionNumber><AccessionNumber>4RF1</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>10</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D025801">Ubiquitin</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.2</RegistryNumber><NameOfSubstance UI="D010206">Papain</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D020816" MajorTopicYN="N">Amino Acid Motifs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D057809" MajorTopicYN="N">HEK293 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