The structure of cytomegalovirus immune modulator UL141 highlights structural Ig‐fold versatility for receptor binding
Identifieur interne : 001C17 ( Istex/Corpus ); précédent : 001C16; suivant : 001C18The structure of cytomegalovirus immune modulator UL141 highlights structural Ig‐fold versatility for receptor binding
Auteurs : Ivana Nem Ovi Ová ; Dirk M. ZajoncSource :
- Acta Crystallographica Section D [ 1399-0047 ] ; 2014-03-01.
Abstract
Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long‐term persistence in the host, Human cytomegalovirus (HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell‐surface expression of both the NK cell‐activating ligand CD155 as well as the TRAIL death receptors (TRAIL‐R1 and TRAIL‐R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head‐to‐tail dimerization interface. A `dimerization‐deficient' mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL‐R2 or CD155 while losing the ability to cross‐link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL‐R2 further identified a mobile loop that makes intimate contacts with TRAIL‐R2 upon receptor engagement. Superposition of the Ig‐like domain of UL141 on the CD155 ligand T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig‐like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock‐and‐key' interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X6G `lock' motif for CD155 binding as well as conservation of the TRAIL‐R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.
Url:
DOI: 10.1107/S1399004713033750
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ISTEX:DC310E2631F5FE29F6D764DA600FA7CBB66F6454Le document en format XML
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Superposition of the Ig‐like domain of UL141 on the CD155 ligand T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig‐like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock‐and‐key' interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X6G `lock' motif for CD155 binding as well as conservation of the TRAIL‐R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ivana Nemčovičová</name></json:item><json:item><name>Dirk M. 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Structural comparison of unliganded UL141 with UL141 bound to TRAIL‐R2 further identified a mobile loop that makes intimate contacts with TRAIL‐R2 upon receptor engagement. Superposition of the Ig‐like domain of UL141 on the CD155 ligand T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig‐like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock‐and‐key' interactions. 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Zajonc, e‐mail: <email>dzajonc@liai.org</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:AYD2.AYD2XB5073.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 4 April 2013, accepted 13 December 2013</unparsedEditorialHistory><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="wordTotal" number="0"></count><count type="referenceTotal" number="0"></count><count type="linksCrossRef" number="0"></count><count type="linksPubMed" number="0"></count></countGroup><titleGroup><title type="main">The structure of cytomegalovirus immune modulator UL141 highlights structural Ig‐fold versatility for receptor binding</title><title type="short">Cytomegalovirus immune modulator UL141</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1"><personName><givenNames>Ivana</givenNames><familyName>Nemčovičová</familyName></personName></creator><creator creatorRole="author" xml:id="cr2"><personName><givenNames>Dirk M.</givenNames><familyName>Zajonc</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="US"><unparsedAffiliation>Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="SK"><unparsedAffiliation>Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, SK 84505 Bratislava, Slovakia</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">cytomegalovirus</keyword><keyword xml:id="k2">UL141</keyword><keyword xml:id="k3">TRAIL‐R2</keyword><keyword xml:id="k4">CD155</keyword><keyword xml:id="k5">immune modulators</keyword></keywordGroup><supportingInformation><p>PDB reference: <link href="http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4jm0">
UL141, 4jm0</link></p><p>Supporting Information. DOI: <link href="http://dx.doi.org/10.1107/S1399004713033750/xb5073sup1.pdf">10.1107/S1399004713033750/xb5073sup1.pdf</link></p></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><p>Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long‐term persistence in the host, <i>Human cytomegalovirus</i> (HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell‐surface expression of both the NK cell‐activating ligand CD155 as well as the TRAIL death receptors (TRAIL‐R1 and TRAIL‐R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head‐to‐tail dimerization interface. A `dimerization‐deficient' mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL‐R2 or CD155 while losing the ability to cross‐link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL‐R2 further identified a mobile loop that makes intimate contacts with TRAIL‐R2 upon receptor engagement. Superposition of the Ig‐like domain of UL141 on the CD155 ligand T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig‐like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock‐and‐key' interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)<i>X</i><sub>6</sub>G `lock' motif for CD155 binding as well as conservation of the TRAIL‐R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>The structure of cytomegalovirus immune modulator UL141 highlights structural Ig‐fold versatility for receptor binding</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Cytomegalovirus immune modulator UL141</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>The structure of cytomegalovirus immune modulator UL141 highlights structural Ig‐fold versatility for receptor binding</title></titleInfo><name type="personal"><namePart type="given">Ivana</namePart><namePart type="family">Nemčovičová</namePart><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dirk M.</namePart><namePart type="family">Zajonc</namePart><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>International Union of Crystallography</publisher><place><placeTerm type="text">5 Abbey Square, Chester, Cheshire CH1 2HU, England</placeTerm></place><dateIssued encoding="w3cdtf">2014-03-01</dateIssued><edition>Received 4 April 2013, accepted 13 December 2013</edition><copyrightDate encoding="w3cdtf">2014</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">0</extent><extent unit="tables">0</extent><extent unit="formulas">0</extent><extent unit="references">0</extent><extent unit="linksCrossRef">0</extent><extent unit="words">0</extent></physicalDescription><abstract lang="en">Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long‐term persistence in the host, Human cytomegalovirus (HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell‐surface expression of both the NK cell‐activating ligand CD155 as well as the TRAIL death receptors (TRAIL‐R1 and TRAIL‐R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head‐to‐tail dimerization interface. A `dimerization‐deficient' mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL‐R2 or CD155 while losing the ability to cross‐link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL‐R2 further identified a mobile loop that makes intimate contacts with TRAIL‐R2 upon receptor engagement. Superposition of the Ig‐like domain of UL141 on the CD155 ligand T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig‐like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock‐and‐key' interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X6G `lock' motif for CD155 binding as well as conservation of the TRAIL‐R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.</abstract><subject lang="en"><genre>keywords</genre><topic>cytomegalovirus</topic><topic>UL141</topic><topic>TRAIL‐R2</topic><topic>CD155</topic><topic>immune modulators</topic></subject><relatedItem type="host"><titleInfo><title>Acta Crystallographica Section D</title></titleInfo><titleInfo type="abbreviated"><title>Acta Crystallographica D</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><note type="content"> PDB reference: UL141, 4jm0 Supporting Information. DOI: 10.1107/S1399004713033750/xb5073sup1.pdf PDB reference: UL141, 4jm0 Supporting Information. DOI: 10.1107/S1399004713033750/xb5073sup1.pdf</note><identifier type="ISSN">1399-0047</identifier><identifier type="eISSN">1399-0047</identifier><identifier type="DOI">10.1111/(ISSN)1399-0047</identifier><identifier type="PublisherID">AYD2</identifier><part><date>2014</date><detail type="volume"><caption>vol.</caption><number>70</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>851</start><end>862</end></extent></part></relatedItem><identifier type="istex">DC310E2631F5FE29F6D764DA600FA7CBB66F6454</identifier><identifier type="ark">ark:/67375/WNG-ZXXZ4SQV-7</identifier><identifier type="DOI">10.1107/S1399004713033750</identifier><identifier type="ArticleID">AYD2XB5073</identifier><accessCondition type="use and reproduction" contentType="copyright">International Union of Crystallography, 2014</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-L0C46X92-X">wiley</recordContentSource><recordOrigin>Converted from (version ) to MODS version 3.6.</recordOrigin><recordCreationDate encoding="w3cdtf">2019-11-13</recordCreationDate></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-ZXXZ4SQV-7/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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