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

Descripción del proyecto

El complejo proteico de los canales de potasio con dos poros como diana terapéutica en el tratamiento antineoplásico

La proteína TASK-3 forma parte de la familia de los canales de potasio con dos poros, descubierta recientemente, responsable de mantener el potencial de reposo de la membrana. Está implicada en enfermedades neurológicas y estudios recientes han demostrado su expresión anormal en células de cáncer colorrectal, pulmonar y de mama. El proyecto InterTask, financiado con fondos europeos, tiene como objetivo completar el análisis funcional y estructural del complejo proteico entre la TASK-3 y el KCC2, un cotransportador de cationes que afecta al transporte de TASK-3 hacia la membrana. La información estructural sobre este complejo proteico revelará las zonas de la TASK-3 implicadas en las interacciones entre proteínas como posibles dianas para el descubrimiento de fármacos que modulen la actividad del canal iónico.

Objetivo

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.