%0 Journal Article %T Interactions of the protein tyrosine phosphatase PTPN3 with viral and cellular partners through its PDZ domain: insights into structural determinants and phosphatase activity %T Interactions de la protéine tyrosine phosphatase PTPN3 avec des partenaires viraux et cellulaires via son domaine PDZ : aperçu des déterminants structuraux et de l'activité de la phosphatase %+ Récepteurs Canaux - Channel Receptors %+ Ecole Doctorale Complexité du Vivant (ED515) %+ Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform) %+ Cristallographie (Plateforme) - Crystallography (Platform) %+ Institut de biologie physico-chimique (IBPC (FR_550)) %A Genera, Mariano %A Colcombet-Cazenave, Baptiste %A Croitoru, Anastasia %A Raynal, Bertrand %A Mechaly, Ariel %A Caillet, Joël %A Haouz, Ahmed %A Wolff, Nicolas %A Caillet-Saguy, Célia %Z The project has received fundings from ANRS (ANRS 22167 AP 2021-2 CAILLET-SAGUY). MG was part of the Pasteur-Paris University (PPU) International PhD Program. BC-C was supported by The Fondation pour la Recherche Médicale (grant No FDT202106013076). %< avec comité de lecture %@ 2296-889X %J Frontiers in Molecular Biosciences %I Frontiers Media %V 10 %P 1192621 %8 2023-05-02 %D 2023 %R 10.3389/fmolb.2023.1192621 %M 37200868 %K PDZ domains %K PDZ-binding motif %K PDZome %K X-ray crystallography %K bioinformatics %K enzyme kinetics %K protein tyrosine phosphatase PTPN3 %K protein-protein interaction. %Z Life Sciences [q-bio]Journal articles %X The human protein tyrosine phosphatase non-receptor type 3 (PTPN3) is a phosphatase containing a PDZ (PSD-95/Dlg/ZO-1) domain that has been found to play both tumor-suppressive and tumor-promoting roles in various cancers, despite limited knowledge of its cellular partners and signaling functions. Notably, 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 respectively. This study focuses on the interactions between the PTPN3 PDZ domain (PTPN3-PDZ) and PBMs of viral and cellular protein partners. We solved the X-ray structures of complexes between PTPN3-PDZ and PBMs of E6 of HPV18 and the tumor necrosis factor-alpha converting enzyme (TACE). We provide new insights into key structural determinants of PBM recognition by PTPN3 by screening the selectivity of PTPN3-PDZ recognition of PBMs, and by comparing the PDZome binding profiles of PTPN3-recognized PBMs and the interactome of PTPN3-PDZ. The PDZ domain of PTPN3 was known to auto-inhibit the protein’s phosphatase activity. We discovered that the linker connecting the PDZ and phosphatase domains is involved in this inhibition, and that the binding of PBMs does not impact this catalytic regulation. Overall, the study sheds light on the interactions and structural determinants of PTPN3 with its cellular and viral partners, as well as on the inhibitory role of its PDZ domain on its phosphatase activity. %G English %Z We thank the staff of the crystallography platform at Institut Pasteur for carrying out robot-driven crystallization screening. We thank the Institut Pasteur molecular biophysics platform for the technical help and access to instruments. We thank the Institut Pasteur biological NMR technological platform for access to instruments and help with NMR experiments. We acknowledge synchrotron SOLEIL (Saint-Aubin, France) for granting access to their facility and the staff of Proxima1 for helpful assistance during the data collection and Aurelien thureau and Javier Perez for the SWING beamline. %2 https://pasteur.hal.science/pasteur-04103585/document %2 https://pasteur.hal.science/pasteur-04103585/file/fmolb-10-1192621.pdf %L pasteur-04103585 %U https://pasteur.hal.science/pasteur-04103585 %~ PASTEUR %~ CNRS %~ SORBONNE-UNIVERSITE %~ SORBONNE-UNIV %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ SU-TI %~ ALLIANCE-SU %~ FRM %~ CHAN-RECEPTORS %~ PASTEUR_UMR3571