Plates-Formes de Recherche en Neurosciences

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Jacques Fantini

Research interests

Since 2002, the main objective of our research is to characterize the molecular mechanisms controling lipid-lipid and lipid-proteins interactions in biological membranes and the consequences of these interactions for membrane functions.

Since 2002, the main objective of our research is to characterize the molecular mechanisms controling lipid-lipid and lipid-proteins interactions in biological membranes and the consequences of these interactions for membrane functions. We have discovered a universal proteic fold, referred to as the sphingolipid binding domain (SBD), which appears to be involved in the interaction between a wide range of cellular and pathogen-associated proteins and membrane microdomains enriched in cholesterol and sphingolipids (i.e. lipid rafts). This domain has been identified in the prion protein (PrP), the HIV-1 surface envelope glycoprotein (gp120) and Alzheimer’s beta amyloid peptide. It consists of a turn with at least one solvent-exposed aromatic residue. The molecular interaction between the protein and the glycosphingolipids (GSL) is driven by a geometric fit involving the aromatic ring and the apolar surface of a galactosyl group belonging to the GSL (CH-Pi stacking interaction). By combining two computational approaches, i.e. structure similarity searches and molecular dynamics modeling techniques, we have developed an algorithm for the detection of SBD folds by a simple analysis of amino acid sequences of proteins. Moreover, we have proposed that raft sphingolipids could act as chaperones for membrane proteins, helping them to acquire or maintain their native configurations. This concept may be relevant to the α→ β conformational changes associated with neurodegenerative pathologies (Alzheimer, Creutzfeldt-Jakob) ou infectious diseases (prions, HIV, pathogenic bacteria, toxins). Our experience in this field will allow us to collaborate with other teams of the CRN2M (especially with José Boucraut) on neuroscience projects. Several collaborating programs, involving french and foreign laboratories are currently under progress.

Currently, our team is composed of biochemists (Henri Chahinian, Jacques Fantin), molecular biologists (Nouara Yahi, Xiao-Jun Guo), cellular biologists (Marc Maresca, Nadira Taïeb, Roselyne Tournaire) and a physiologist (Eric Di Pasquale). All the members of the team share the same interest for the study of membrane-dependent processes, at several levels of investigations (from the molecular to the physiological levels). Given our long term and robust experience of biological membrane research, we have developed a new program focused on the regulatory functions of lipids in the nervous system. Vegetative functions will be particularly studied, as it is now well established that lipid mediators belonging to the endocannabinoid family (e.g. anandamide) are involved in the control of food intake. However, the neurobiological mechanisms associated with these regulatory pathways are not well understood. The originality of our approach is to take into account the peculiar physicochemical nature of lipid mediators (insolubility in water, requirement of proteic transporters, molecular interactions with other lipids in micellar of membrane phases) at each level of investigation (molecular, cellular, and physiological).

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