Description du projet
Le complexe protéique des canaux potassiques à deux pores comme cible thérapeutique dans le traitement du cancer
La protéine TASK-3 est un membre de la famille des canaux potassiques à deux pores, récemment découverte, qui assure le maintien du potentiel de repos de la membrane. Elle est impliquée dans les maladies neurologiques et des études récentes ont mis en évidence l’expression aberrante de TASK-3 dans les cellules cancéreuses du sein, du poumon et de l’appareil colorectal. Le projet InterTask, financé par l’UE, entend effectuer une analyse structurelle et fonctionnelle du complexe constitué de TASK-3 et du co-transporteur de cations KCC2, qui joue sur le transport de TASK-3 vers la membrane. Les informations structurelles sur le complexe permettront de déterminer les régions de TASK-3 impliquées dans les interactions protéine-protéine, constituant des cibles potentielles pour la découverte de médicaments visant à moduler l’activité des canaux ioniques.
Objectif
TASK-3 is a potassium channel member of the recently discovered two-pore potassium channels family (K2P) responsible for the background current maintaining the membrane resting potential. TASK-3 is involved in several neurological diseases but recent studies pointed out its oncogenic potential. TASK-3 aberrant expression was detected in breast, lung and colorectal cancer cells. This research proposal aims at 1) generate antibodies that can directly reduce TASK-3 function. The potency, the binding mode of the best antibodies will be characterized functionally and structurally to provide an atomic-resolution view of the mechanism of binding, paving the way for antibody engineering. The structural approach will also produce the three-dimensional structure of TASK-3, which will deepen our understanding on the biophysical properties of this channel and its involvement in several other pathologies. 2) Reduce TASK-3 activity by understanding the molecular basis of its trafficking to the membrane. The project aims at providing a structural and functional analysis of the complex between TASK-3 and the cation cotrasporter KCC2, a recently identified partner that affect TASK-3 trafficking to the membrane. Structural information on the complex will uncover regions of the channel involved in binding protein partners, opening the possibility of pursuing these protein-protein interactions surfaces as targets for drug discovery, with the ultimate goal of modulating ion channel activity. I will undertake a multidisciplinary study that spans protein biochemistry, structural biology, electrophysiology and antibody engineering. The project tackles – side by side - basic science questions (ion channel structure and regulation) and translational research (antibody-based therapy). It offers a molecular understanding of the structural and biophysical properties of TASK-3 -currently unavailable- and opens the venue to the therapeutic targeting of this ion channel.
Champ scientifique
Not validated
Not validated
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural scienceschemical sciencesinorganic chemistryalkali metals
- medical and health sciencesclinical medicineoncologycolorectal cancer
- medical and health sciencesbasic medicinepathology
Programme(s)
Régime de financement
MSCA-IF-EF-CAR - CAR – Career Restart panelCoordinateur
27100 Pavia
Italie