STRUCTURE OF MACROMOLECULAR TARGETS UNIT
Research in my laboratory is focused on understanding the molecular mechanisms and cellular functions of proteins and how their defects can lead to disease. We are particularly interested in explaining protein malfunction, in identifying disease-causing variants, and in helping to find new therapeutic strategies to amend the activity of the faulty proteins.
My group’s approach relies on a mixture of biochemical and biophysical methods to define the structure, function and evolution of these macromolecular targets. Protein engineering, X-ray crystallography and enzymology form the core of our research approach, but we increasingly combine these methods with single-particle electron microscopy, CRISPR/Cas tools, fluorescence microscopy and cellular assays. We do all what is needed to get answers and ask better questions. Working in our lab entails this interdisciplinary approach, being trained in many different technical skills and sharing a culture of hard work and cooperation.
Since the group started in 2010, one of our objectives has been to decipher the architecture and functioning mechanisms of CAD, a multifunctional mega-enzyme responsible for the initiation and control of de novo synthesis of pyrimidine nucleotides. Our efforts have allowed us to characterize the structures of the dihydroorotase and aspartate transcarbamoylase domains of CAD, to define their catalytic and regulatory mechanisms, and to understand how these domains nucleate the organization of CAD into a very large hexameric particle. Our efforts are now directed towards the characterization in full detail of this complex molecular machine and to understand how it functions inside the cell. Also, since the discovery in 2015 that defects in CAD cause a rare and potentially lethal congenital disease, my group has been involved in the identification of pathogenic variants of CAD, helping in the diagnosis of children affected by this illness.
We extend our studies to other disease-related proteins involved in diverse processes such as glycosylation pathways or control of gene expression.