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

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.

Coordinator

UNIVERSITA DEGLI STUDI DI PAVIA
Net EU contribution
€ 275 209,92
Address
Strada nuova 65
27100 Pavia
Italy

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Region
Nord-Ovest Lombardia Pavia
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00