Nucleic acid and small molecule recognition by Smad transcription factors and co-factors

Abstract

[eng] Tumour progression largely depends on the signalling networks that direct cell viability, growth and dissemination (metastasis). Transforming growth factor beta (TGF-β) and Bone Morphogenetic Protein (BMP) are cytokines that induce a plethora of physiological functions in all vertebrates, by activating or repressing various signal transducers. One of these is the Smad family of transcription factor proteins, which play an essential role in early embryogenesis, development, cell immunity, homeostasis, tissue repair and many other essential processes during human life. Mutations in the TGF-β signalling components (including Smads) inactivate the cell’s tumour suppression functions, facilitating the survival of cancer cells.

Upon activation by the receptor, Smads form active homo- and hetero- trimeric complexes to interact with DNA sequences (promoters, enhancers) proteins (other transcription factors, co-activators or co-repressors), and also with RNAs. Smad-RNA complexes were reported in the scientific and medical literature; however, this research was largely carried out on a cellular level and the exact details of these interactions remain poorly understood. I have been working on the characterization of Smad-RNA complex formation. I have also determined the structure of a C2 domain present in NEDD4-L, one of the ubiquitin ligases that degrade Smad proteins In a different line of research, which is aimed at defining new targets for drug screening, I determined the structure of (among others) the protein Deadhead, belonging to the lethal(3)malignant brain tumour signature genes and responsible for the development and sex determination in D. melanogaster and several structures of a p38α (MAPK14) kinase, bound to compounds that regulate its function in cells. This work will pave the way for the future optimisation of these compounds to improve their pharmacological properties.