#IDIBELLseminars: Structural insights into TGF beta signaling

SMAD proteins are highly conserved transcription factors that act as downstream effectors of Transforming Growth Factor Beta (TGFβ) signalling. This cascade plays key roles in embryonic development, tissue regeneration, immune system maintenance and neuroprotection. R-SMADs and SMAD4 are modular proteins of around 50 kDa that share a common architecture; two globular domains (MH1 at the N-terminus and MH2, at the C-terminus) connected via a flexible and partially structured linker. In healthy conditions, external TGFβ stimuli induce the pathway’s receptors to phosphorylate two serine residues at the C-terminus of R-SMADs. Thus, these proteins are activated and form heterotrimers with Smad4. These complexes constitute the transcriptionally active units that translocate into the nucleus and, together with other cofactors, drive gene expression. Defects in the TGFβ cascade are linked to diseases. Mutations in SMAD2 and SMAD4 inactivate the pathway’s tumour suppressor function in cancer and de novo single point mutations cause developmental pathologies, including cardiovascular disorders and Myhre Syndrome.
Our laboratory has been working on SMADs for the last ten years. During these years, we have determined several complexes of the MH1 domains bound to DNA, and of the linkers bound to activators and ubiquitin ligases. Very recently, we developed a multidisciplinary approach that combines X-Ray structures, NMR information, MD simulations and SAXS data, has resulted in the integrative description of the conformational landscape and stoichiometry of isolated SMAD2 and SMAD4 full-length proteins in solution. In this conference, I will present our recent advances in the structures of SMAD proteins and also of FoxH1, one of its cofactors, and whose DNA-interacting domain structure we have recently unveiled. Combined with programs of screening and chemical biology these novel structural insights are aiding in the development of potential novel therapies for cancer and Myhre Syndrome.

Hosted by Francesc Ventura – Cell signalling and bone biology

I graduated in Chemistry in 1989 and obtained the PhD in 1993, in the field of Organic Chemistry and Natural Products (Universidad of Salamanca). In 1993, I moved to the EMBL in Heidelberg as a Post-doctoral researcher in structural biology, in the group of Prof. Hartmut Oschkinat. During this time, I characterized the structures of several key signaling protein domains (PH and WW domains) and of the double stranded RNA binding domain, —the first of their kind—. Our results revealed how these domains adopted new folds, with implications on their interactions with ligands and function. We also succeeded in the de novo design of a WW domain, and developed a protocol for the determination of protein structures in solution.
In 1998, I started my career as an independent scientist, at the EMBL in Heidelberg, thanks to a Staff-Scientist position that I won in a competitive call. In 2002, I moved to the IRB Barcelona upon winning an ICREA research professor position where I’ve been working since. Over the last decade, a large part of my lab has been devoted to clarifying the role of Smad transcription factors in TGFβ signaling. Our long-term aim is to illustrate (with our structures) the complete picture of how full-length Smad complexes transmit TGF-β signaling, regulate gene expression and cell fate. In collaboration with the gynecological oncology group Santa Creu i Sant Pau Hospital, Barcelona, we also aim to determine the probability of relapse and metastasis of gynecological Cancer patients using artificial intelligence and data from biopsies as well as data deposited in public data bases.
I also participate in the project CALIPER: Linking research and innovation for gender equality in the fields of research. Funded by H2020_EU.