BECAS MAX PLANCK / FUNDACIÓN BUNGE Y BORN / FUNDACIÓN WILLIAMS
Epigenetic role of 14-3-3 proteins and their interaction with the histone H3
Anselmo Daniel Reggiardo
Chemical Genomics Centre, Max Planck institute
The ability to detect extracellular stimuli and execute the appropriate response is crucial to all cellular functions. This response is accomplished by the transduction of signals from cell surface to the nucleus. A central goal in the signaling field is the identification of physiologically relevant targets of transduction pathways. To that end, much attention has been focused on the mechanistic action of protein complexes with multiple histone-modifying enzymes which ultimately influence gene expression. Gene expression is regulated mainly at the level of transcription initiation. Particularly, the activation of gene expression requires the recruitment of specialized proteins that, among other posttranslational modifications, phosphorylate the histone H3. This covalent modification of histone tails influence the binding of transcription regulators and accordingly modulate gene expression. The phosphorylation of histone H3 at the serine 10 is accompanied by the recruitment of members of the 14-3-3 protein family. This phosphorylation event triggers a signal for the recruitment of a second enzyme which, in turn, acetylates the same histone molecule tail. An important parameter of 14-3-3 interaction with histone H3 is the conformational stabilization by several intramolecular interactions, like salt and hydrogen bridges. However, the role of 14-3-3-histone H3 interaction is far from being clear. Our goal in this project is to design and use specific small molecules aiming to affect this interaction as valuable tools to reveal the participation of 14-3-3 proteins in the activation of transcription.