Project description
The two-pore potassium channel protein complex as a therapeutic target in cancer treatment
TASK-3 protein is a member of the recently discovered two-pore potassium channels family responsible for maintaining the membrane resting potential. It is implicated in neurological diseases, and recent studies have demonstrated TASK-3 aberrant expression in breast, lung and colorectal cancer cells. The EU-funded InterTask project aims to complete a structural and functional analysis of the complex between TASK-3 and the cation co-transporter KCC2 that affects TASK-3 trafficking to the membrane. Structural information on the complex will uncover TASK-3 regions involved in protein-protein interactions as potential targets for drug discovery to modulate ion channel activity.
Objective
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.
Fields of science
- 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)
Funding Scheme
MSCA-IF-EF-CAR - CAR – Career Restart panelCoordinator
27100 Pavia
Italy