Research / Scientific departments / Structural Biology and Chemistry / Units and Groups / Nuclear Magnetic Resonance of Biomolecules / Research
Signalling and Molecular Interactions
(Nicolas Babault, Florence Cordier, Pierre Maisonneuve, Elouan Terrien & Nicolas Wolff)
The control of neuronal death and survival by the Rabies virus glycoprotein
Since 2006, our team has been interested in elucidating the molecular mechanisms of death and survival of neurons infected by different strains of Rabies virus. The project is a close collaboration with a complementary team from the Institut Pasteur, the Unité de Neuroimmunologie Virale headed by Dr Monique Lafon for the in cellulo and in vivo experiments.
Rabies virus (RABV) is a pathogen that is well adapted to the mammalian nervous system where it infects neurons exclusively. Pathogenic (virulent) RABV strains favour neuron survival preserving the integrity of neuron and therefore its dissemination, whereas non-pathogen (attenuated) strains lead to neuron apoptosis. A single mutation located in the C-terminal domain of G protein (CytoG) controls the death/survival balance of the infected neuroblastoma. This change is sufficient to drastically affect the nature of the neuronal partners interacting with the very C-terminus sequence of these G proteins. CytoG encodes a PDZ binding site (PDZ-BS), encompassing the critical mutation.
Neuron survival requires selective association of the PDZ-BS with the PDZ domain of two closely related serine-threonine kinases (MAST1 and MAST2). The single amino acid change in the PDZ-BS triggering neuronal death, allows G protein to recruit additional PDZ partners, notably a tyrosine-phosphatase, PTPN4. It is now established that MAST2 functions as an inhibitor of neurosurvival and PTPN4 as an inhibitor of cell death. We postulated that RABV G proteins antagonize PTPN4 and MAST2 functions by disrupting the interactions of their PDZ domains with their respective cellular ligands. We performed extensive biophysical and structural characterizations of the complexes formed by the viral motives or endogenous ligands and the PDZ domains of MAST2 or PTPN4, which support this hypothesis.
Viruses are art masters in manipulating the survival and the death of the host cells they infect. Thus viral genomes are highly promising sources to discover new survival or death sequences and sustained robust pathways that may lead to the development of new neuroprotective compounds and potential anticancer molecules. Our project addresses fundamental aspects of neuronal cell death and survival mechanisms as well as more applied issues. We plan to characterize signalling pathways which are perturbed by sequences from viral origin, to design optimized pro-survival and pro-death sequences and drugs, to understand their mechanism of action, and to validate neuroprotective activity in neurons and models of human neurodegenerative diseases and anti-proliferative capacity in several glioblastoma cell lines and in the xenograft model.
Structural and functional studies of NEMO, a regulatory protein of the NF-κB pathway
(Florence Cordier in collaboration with Fabrice Agou from the Structural and Biochemical Biology Unit)
NEMO is a central regulatory protein of the NF-κB signaling pathway, notably involved in early inflammatory and immune responses and in regulation of apoptosis as well as oncogenesis. In order to understand the molecular mechanism by which NEMO participates in NF-κB activation and to facilitate the elaboration of anti-inflammatory and anti-cancer drugs targeting NEMO, we are studying the biophysical, structural and functional characteristics of the C-terminal regulatory domains of NEMO and their interactions with biological partners and with small inhibitory molecules.