Cell Signalling & Trafficking Structures

BIOGRAPHY

CURRENT POSITION:
Investigator and Group Leader, Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique (CNRS)

RESEARCH INTERESTS:
Small GTP-binding proteins form a superfamily of 'switch' proteins which are essential regulators of signal transduction, organization of the cytoskeleton and cellular traffic. Their active form, which binds GTP, interacts with cellular partners called 'effectors' to which they transmit signals of action. The activity of small GTP-binding is controlled in space and time by three main classes of proteins, which regulate the alternation between their inactive, GTP-bound form, and their active form: Guanine nucleotide exchange factors (GEFs), which activate small GTP-binding proteins by stimulating the dissociation of the tightly bound GDP nucleotide; GTPase Activating Proteins (GAPs), which terminate the signal by stimulating the hydrolysis of GTP; Guanine Nucleotide Dissociation Inhibitors (GDIs), which partition the Rho and Rab subfamilies between membranes and cytosol.

Small G proteins, their regulators and their effectors are combined in multiple ways to generate the specificity of cellular responses. Deregulation of small G proteins is involved in various human diseases such as cancer or infection by pathogens, where they are potential targets for therapeutic intervention.

We study protein-protein interactions involved in the regulation of small GTP-binding proteins of the Arf (cellular traffic) and Rho/Rac (cell morphology) families. We develop a combined approach of structural and cellular biology, which offers novel perspectives for the conception of experiments and their interpretation. Our recent results have focused on the following themes:
• Structural and biochemical bases for the activation of Arf proteins by their GEFs (cytohesins and GBF1/BIG families)
• Characterisation of GEF inhibitors of various types (natural or synthetic small molecules, peptides)
• Concept of interfacial inhibition at protein-protein interfaces
• Cellular characterisation of RhoGDI3, an unconventional RhoGDI