Therapeutic molecules and druggable sites to suppress aberrant ion channel activity in cancer.

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.