Acetylation of lysine residues (Kac) is one of the most frequently occurring post-translational modifications (PTMs) which control gene transcription and a vast array of diverse cellular functions. Acetylation levels are reversibly maintained by a group of enzymes, the histone acetyl-transferases (HATs) and histone deacetylases (HDACs) that “write” and “erase” acetylation marks on histones. Deregulation of acetylation levels has been associated with the development of many diseases and enzymes regulating acetylation have emerged as interesting targets for drug discovery. Inhibitors of HDACs for instance have potent anticancer activities, with remarkable tumour specificity and show promising results in clinical trials in particular for haematological malignancies.
To date little is known of the “reading” process of acetylation marks. Bromdomains (BRDs) are the only known protein recognition module that selectively targets ε-N-acetylation of lysines. The human proteome encodes over 40 proteins that contain more than 60 diverse BRDs. Despite their low sequence identity all BRDs share a conserved fold comprising a left-handed bundle of four alpha helices, linked by diverse loop regions that contribute to substrate specificity. Co-crystal structures with substrate peptides showed that Kac is recognized by a central hydrophobic cavity and is anchored by a hydrogen bond with an asparagine residue present in most BRDs. However, the substrates (e.g. the acetylated sequences that are specifically recognized) of most BRDs are largely unknown.
As part of the structural genomics initiative we seek to structurally characterize all human BRDs. We have established recombinant expression systems that yield soluble protein of high purity for more than two thirds of the human family of BRDs. Furthermore, we are investigating a number of interacting Kac-containing linear motifs, trying to elucidate the structural mechanisms that determine substrate recognition.
As part of the epigenetic probe initiative, we established that the Kac docking pocket is an attractive binding site for the development of inhibitors. We are supporting the small molecule and ligand screening effort by supplying highly pure proteins to the screening group. In parallel we seek to establish highly reproducible crystallization systems so that potential acetyl-mimetic ligands can be structurally characterized, thus helping understand their mode of interaction with BRDs. Ultimately we aim to generate high quality potent and selective chemical probes that can be used to elucidate the biological function of individual bromodomain containing proteins.
Sarah trained in cell biology in France, first receiving her B.Sc. from L’Institut Catholique d’Etudes Superieures in 1995 then her PhD in 2001 from the University of Poitiers working on the analysis and characterization of factors controlling water and sugar accumulation in grapes during the maturation process. She carried her post-doctoral training at the University of Kalmar in Sweden (2001-2006) and was awarded a Marie Curie Fellowship in 2002 working on sesquiterpene synthases, enzymes involved in the biosynthetic pathway of the potent antimalarial drug Artemisinin. She joined Opher Gileadi’s group in the SGC in 2007 as a post doctoral researcher where she gained experience in high throughput cloning and later Stefan Knapp’s group in 2009 working on the biology and structural characterization of epigenetic readers of the bromodomain family.