Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 27, Pages 7958-7962Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201502646
Keywords
antitumor agents; human papillomavirus; inhibitors; peptides; protein engineering
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Funding
- CNRS, Universite de Strasbourg
- Association pour la Recherche contre le Cancer (ARC) [3171]
- Agence Nationale de la Recherche [ANR-MIME-2007 EPI-HPV-3D]
- National Institute of Health (NIH) [R01A134737]
- Ligue contre le Cancer and Alsace contre le cancer
- ANR [MIME-2007 EPI-HPV-3D]
- NIH [R01A134737]
- Ligue contre le Cancer
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The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6proteins tested but not to low-risk mucosal or cutaneous HPVE6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers.
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