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Epstein Barr virus EBNA2 : interactions of intrinsically disordered proteins with host cell factors.

Abstract : It was recently reported that the physiological interaction between the nuclear protein SMRT and the cellular transcription factor STAT3 could be disrupted by the Epstein-Barr-virus protein EBNA2. Binding of SMRT to STAT3 decreases its transcriptional activity. EBNA2 releases SMRT from this complex and therefore enhances the transcription of both host and viral STAT3 regulated genes. STAT3 regulates several immunosuppressive as well as pro-proliferative and anti-apoptotic effects in the host organism and so may have importance for the viral survival strategy of Epstein-Barr-virus. Both EBNA2 and SMRT are intrinsically disordered proteins (IDPs) in common with about one third of all eukaryotic proteins and 70% of cancer-related. Despite their abundance, our understanding of how they function is limited, in part due to difficulties in production of stable samples in the large quantities necessary for structural and biophysical studies. The EPRIT technology was used to overcome these problems and generate well-behaving and -expressing EBNA2 and SMRT fragments. These fragments covered large parts of the EBNA2 and SMRT genes and were in a suitable size for NMR experiments. This enabled interaction studies of these proteins with STAT3. As both proteins are mainly intrinsically disordered all interaction data were analysed with attention to the disordered properties of both proteins. In order to complement the interaction data all fragments used for the interaction studies were as well characterized as IDPs using biochemical and biophysical methods. Fragments of both proteins, EBNA2 and SMRT together with the STAT3 dimer were subjected to binding analysis using various biophysical methods. The kinetics of the binding could be determined and the binding regions could be narrowed down to the amino acid level. Because of its biological significance and higher affinity interaction the EBNA2-STAT3 part was prioritized and first preliminary results investigating the interaction in mammalian cells could be obtained. Also, the interaction between EBNA2 and other cellular proteins was studied briefly. The obtained results aim to improve our understanding of how EBV succeeds to persist lifelong in the host organism.
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Eva-Maria Geenen. Epstein Barr virus EBNA2 : interactions of intrinsically disordered proteins with host cell factors.. Biochemistry, Molecular Biology. Université de Grenoble, 2013. English. ⟨NNT : 2013GRENV055⟩. ⟨tel-01555490⟩



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