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Structural and functional study of the human phosphatase PTPN3 and its interaction with oncogenic viruses

Abstract : The human protein tyrosine phosphatase non-receptor type 3 (PTPN3) is a PDZ (PSD-95/Dlg/ZO-1) domain-containing phosphatase with a tumor-suppressive or a tumor-promoting role in many cancers, although its role in cell signalling is still unclear. Interestingly, the high-risk genital human papillomavirus (HPV) types 16 and 18 and the hepatitis B virus (HBV) target the PDZ domain of PTPN3 through PDZ-binding motifs (PBMs) in their E6 and HBc proteins. Here, I report a detailed study of the interactions between the PDZ domain of PTPN3 and its cellular and viral ligands. First, we combined biophysical, NMR and X-ray experiments to investigate the structural and functional properties of the PDZ domain of PTPN3 and its interaction with the E6 PBM. We then extended our structural study of PTPN3-PDZ to other cellular and viral partners, and gained insights into the main structural determinants of recognition of PBMs. We then focused on the HBV HBc protein. We screened a library of human PDZ-containing proteins for HBc binders and identified 28 cellular HBc-interacting partners, most of which are involved in cell polarity. We confirmed that PTPN3 can bind the HBc PBM in the context of the viral capsid, and we showed that viral PBMs interact with PTPN3-PDZ with similar affinities to endogenous PTPN3 ligands. Using HBV-infected hepatocytes we observed that overexpression of PTPN3 has multiple effects on HBV infection. Finally, we investigated the interactome of PTPN3-PDZ to gain insights into the role of this protein in cell signalling and the disruptive effects of HBV.
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Mariano Genera. Structural and functional study of the human phosphatase PTPN3 and its interaction with oncogenic viruses. Biophysics. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS112⟩. ⟨tel-02947211⟩

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