Molecular mechanisms of Mediator complex recruitment by transcription factors.

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• Alexis Verger from Institut de Recherche Interdisciplinaire, Université de Lille
• Thursday 08 May 2014, 14:30-15:30
• Part II Room, Department of Genetics.

If you have a question about this talk, please contact Caroline Newnham.

Hosts: Boris Adryan and Alfonso Martinez-Arias

MED25 is a subunit specific to higher eukaryote Mediator complex, an essential component of the RNA polymerase II general transcriptional machinery. Mediator plays major roles in both basal and activated transcription by interacting with transactivation domains (TADs) of transcriptional activators on the one hand and the RNA polymerase II on the other hand. We recently demonstrated that the TAD of the PEA3 subfamily of ETS transcription factors (ERM, ETV1 and PEA3 ) directly interacts with the ACID /PTOV domain of the Mediator complex subunit MED25 . We have determined the structure of the ACID /PTOV domain by NMR spectroscopy that consists of a closed β-barrel with seven strands and three α-helices, an architecture showing similarities to that of the SPOC domain-like superfamily. The interaction between ERM TAD and MED25 ACID /PTOV domain was characterized by isothermal titration calorimetry (ITC), fluorescence polarization (FP) and NMR . The ERM TAD is disordered in solution but has a propensity to adopt local transient conformations suggesting a folding upon binding mechanism of ERM to MED25 . The relevance of this binding mode for ERM compared to the binding of MED25 to the TAD of the herpes simplex virus transcription factor VP16 will be discussed. Moreover, reporter-gene based assays and siRNA-mediated knockdown approaches revealed that MED25 is important for full activation of ERM -mediated transcription and that MED25 ACID /PTOV domain serves as a docking site on Mediator for the PEA3 subfamily transcriptional activation domain. Finally, our recent efforts to better understand structure and function of higher eukaryotes-specific Mediator subunits will be presented.

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