Interference with the PTEN-MAST2 Interaction by a Viral Protein Leads to Cellular Relocalization of PTEN
| Autor: | Muriel Delepierre, Nicolas Wolff, Zakir Khan, Monique Lafon, Henri Buc, Mireille Lafage, Elouan Terrien, Florence Cordier, Alain Chaffotte, Catherine Simenel, Christophe Prehaud |
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| Přispěvatelé: | Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Neuro-Immunologie Virale, Institut Pasteur [Paris] (IP), This work was supported by grants from the Institut Pasteur, Agence Nationale pour la Recherche, and Institut Carnot Pasteur Maladies Infectieuses. E.T. is a recipient of fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale., We thank P. Roux (Imagopole, Institut Pasteur), P. England, B. Raynal, S. Hoos, E. Frachon, and V. Bondet (Proteopole, Institut Pasteur) for their technical expertise., Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Sorbonne Université (SU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular MESH: Isotope Labeling [SDV]Life Sciences [q-bio] MESH: Neurons PDZ Domains medicine.disease_cause Biochemistry 0302 clinical medicine MESH: Nuclear Magnetic Resonance Biomolecular MESH: PDZ Domains Tensin Neurons 0303 health sciences biology [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Immunohistochemistry MESH: Rabies virus MESH: Cell Survival Isotope Labeling Microtubule-Associated Proteins MESH: Models Molecular MESH: Spectrometry Fluorescence MESH: Cell Line Tumor Microtubule-associated protein G protein Viral protein Cell Survival Phosphatase PDZ domain Blotting Western MESH: Glycoproteins MESH: Binding Competitive Calorimetry Protein Serine-Threonine Kinases Binding Competitive MESH: PTEN Phosphohydrolase MESH: Protein-Serine-Threonine Kinases 03 medical and health sciences Viral Proteins Cell Line Tumor medicine PTEN Gene silencing Humans MESH: Blotting Western [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Calorimetry Molecular Biology Nuclear Magnetic Resonance Biomolecular 030304 developmental biology Glycoproteins MESH: Humans PTEN Phosphohydrolase MESH: Immunohistochemistry Cell Biology Molecular biology MESH: Viral Proteins MESH: Microtubule-Associated Proteins Spectrometry Fluorescence Rabies virus biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Science Signaling Science Signaling, 2012, 5 (237), pp.ra58-ra58. ⟨10.1126/scisignal.2002941⟩ Science Signaling, American Association for the Advancement of Science, 2012, 5 (237), pp.ra58-ra58. ⟨10.1126/scisignal.2002941⟩ |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.2002941⟩ |
| Popis: | International audience; PTEN (phosphatase and tensin homolog deleted on chromosome 10) and MAST2 (microtubule-associated serine and threonine kinase 2) interact with each other through the PDZ domain of MAST2 (MAST2-PDZ) and the carboxyl-terminal (C-terminal) PDZ domain-binding site (PDZ-BS) of PTEN. These two proteins function as negative regulators of cell survival pathways, and silencing of either one promotes neuronal survival. In human neuroblastoma cells infected with rabies virus (RABV), the C-terminal PDZ domain of the viral glycoprotein (G protein) can target MAST2-PDZ, and RABV infection triggers neuronal survival in a PDZ-BS-dependent fashion. These findings suggest that the PTEN-MAST2 complex inhibits neuronal survival and that viral G protein disrupts this complex through competition with PTEN for binding to MAST2-PDZ. We showed that the C-terminal sequences of PTEN and the viral G protein bound to MAST2-PDZ with similar affinities. Nuclear magnetic resonance structures of these complexes exhibited similar large interaction surfaces, providing a structural basis for their binding specificities. Additionally, the viral G protein promoted the nuclear exclusion of PTEN in infected neuroblastoma cells in a PDZ-BS-dependent manner without altering total PTEN abundance. These findings suggest that formation of the PTEN-MAST2 complex is specifically affected by the viral G protein and emphasize how disruption of a critical protein-protein interaction regulates intracellular PTEN trafficking. In turn, the data show how the viral protein might be used to decipher the underlying molecular mechanisms and to clarify how the subcellular localization of PTEN regulates neuronal survival. |
| Databáze: | OpenAIRE |
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