Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination

Mortensen, Franziska; Schneider, Daniel; Barbic, Tanja; Sladewska-Marquardt, Anna; Kühnle, Simone; Marx, Andreas; Scheffner, Martin

Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination

Dateien

Mortensen_0-314735.pdfGröße: 542.22 KBDownloads: 433

Datum

2015

Autor:innen

Mortensen, Franziska

Schneider, Daniel

Barbic, Tanja

Sladewska-Marquardt, Anna

Kühnle, Simone

Marx, Andreas

Scheffner, Martin

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Proceedings of the National Academy of Sciences of the United States of America : PNAS. 2015, 112(32), pp. 9872-9877. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1505923112

Zusammenfassung

Deregulation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with three different clinical pictures. Hijacking of E6AP by the E6 oncoprotein of distinct human papillomaviruses (HPV) contributes to the development of cervical cancer, whereas loss of E6AP expression or function is the cause of Angelman syndrome, a neurodevelopmental disorder, and increased expression of E6AP has been involved in autism spectrum disorders. Although these observations indicate that the activity of E6AP has to be tightly controlled, only little is known about how E6AP is regulated at the posttranslational level. Here, we provide evidence that the hydrophobic patch of ubiquitin comprising Leu-8 and Ile-44 is important for E6AP-mediated ubiquitination, whereas it does not affect the catalytic properties of the isolated catalytic HECT domain of E6AP. Furthermore, we show that the HPV E6 oncoprotein rescues the disability of full-length E6AP to use a respective hydrophobic patch mutant of ubiquitin for ubiquitination and that it stimulates E6AP-mediated ubiquitination of Ring1B, a known substrate of E6AP, in vitro and in cells. Based on these data, we propose that E6AP exists in at least two different states, an active and a less active or latent one, and that the activity of E6AP is controlled by noncovalent interactions with ubiquitin and allosteric activators such as the HPV E6 oncoprotein.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

MORTENSEN, Franziska, Daniel SCHNEIDER, Tanja BARBIC, Anna SLADEWSKA-MARQUARDT, Simone KÜHNLE, Andreas MARX, Martin SCHEFFNER, 2015. Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination. In: Proceedings of the National Academy of Sciences of the United States of America : PNAS. 2015, 112(32), pp. 9872-9877. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1505923112

BibTex

@article{Mortensen2015ubiqu-32626,
  year={2015},
  doi={10.1073/pnas.1505923112},
  title={Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination},
  number={32},
  volume={112},
  issn={0027-8424},
  journal={Proceedings of the National Academy of Sciences of the United States of America : PNAS},
  pages={9872--9877},
  author={Mortensen, Franziska and Schneider, Daniel and Barbic, Tanja and Sladewska-Marquardt, Anna and Kühnle, Simone and Marx, Andreas and Scheffner, Martin}
}

RDF

<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/32626">
    <dc:creator>Schneider, Daniel</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/32626/3/Mortensen_0-314735.pdf"/>
    <dc:creator>Sladewska-Marquardt, Anna</dc:creator>
    <dcterms:issued>2015</dcterms:issued>
    <dcterms:abstract xml:lang="eng">Deregulation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with three different clinical pictures. Hijacking of E6AP by the E6 oncoprotein of distinct human papillomaviruses (HPV) contributes to the development of cervical cancer, whereas loss of E6AP expression or function is the cause of Angelman syndrome, a neurodevelopmental disorder, and increased expression of E6AP has been involved in autism spectrum disorders. Although these observations indicate that the activity of E6AP has to be tightly controlled, only little is known about how E6AP is regulated at the posttranslational level. Here, we provide evidence that the hydrophobic patch of ubiquitin comprising Leu-8 and Ile-44 is important for E6AP-mediated ubiquitination, whereas it does not affect the catalytic properties of the isolated catalytic HECT domain of E6AP. Furthermore, we show that the HPV E6 oncoprotein rescues the disability of full-length E6AP to use a respective hydrophobic patch mutant of ubiquitin for ubiquitination and that it stimulates E6AP-mediated ubiquitination of Ring1B, a known substrate of E6AP, in vitro and in cells. Based on these data, we propose that E6AP exists in at least two different states, an active and a less active or latent one, and that the activity of E6AP is controlled by noncovalent interactions with ubiquitin and allosteric activators such as the HPV E6 oncoprotein.</dcterms:abstract>
    <dc:contributor>Kühnle, Simone</dc:contributor>
    <dc:contributor>Schneider, Daniel</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2016-01-19T13:10:32Z</dc:date>
    <dc:creator>Barbic, Tanja</dc:creator>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:creator>Marx, Andreas</dc:creator>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/29"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:contributor>Sladewska-Marquardt, Anna</dc:contributor>
    <dc:creator>Scheffner, Martin</dc:creator>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:creator>Kühnle, Simone</dc:creator>
    <dc:contributor>Marx, Andreas</dc:contributor>
    <dc:contributor>Barbic, Tanja</dc:contributor>
    <dc:contributor>Mortensen, Franziska</dc:contributor>
    <dc:language>eng</dc:language>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/32626/3/Mortensen_0-314735.pdf"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/29"/>
    <dc:creator>Mortensen, Franziska</dc:creator>
    <dc:rights>terms-of-use</dc:rights>
    <dcterms:title>Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination</dcterms:title>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/32626"/>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2016-01-19T13:10:32Z</dcterms:available>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:contributor>Scheffner, Martin</dc:contributor>
  </rdf:Description>
</rdf:RDF>

Universitätsbibliographie

Ja