Positive selection and structural disruption of KCNA5 by mutation in colorectal cancer

Ion channels play a crucial role in regulating cell proliferation, survival, and migration. However, the functional implications of many ion channel mutations in cancer remain unclear, and conducting electrophysiological characterisation on a large scale is not feasible. Researchers have turned to the mutational landscape of colorectal adenocarcinoma as a functional filter to identify potassium channel mutations that are under positive mutational selection.

Through a dN/dS screen of 16 potassium channels expressed in the large intestine, they discovered that KCNA5 (Kv1.5) is the strongest candidate for selection. The mutations in KCNA5 tend to cluster in the T1 tetramerisation, S1-S4 voltage-sensor, and pore domains, while avoiding the selectivity filter, suggesting that the selection does not favor a loss of conduction.

The observed mutations in the pore region occupy a distinct biophysical space, separate from known C-type inactivation, activation-gate, and toxin-binding mutations. Mutations in the voltage sensor affect gating-charge arginines, while those in the T1 domain fall on inter-subunit interfaces conserved across the KCNA family, potentially destabilizing subunit contacts or domain folding.

Molecular dynamics simulations reveal loss of coordinated interface dynamics and distortion of the local backbone for specific mutations. Transcriptomic analysis of KCNA5-mutant tumors indicates reduced expression of cell-cycle, KRAS-related, and inflammatory pathways, with differences in transcriptional effects induced by mutations in different domains.

These changes are not reproduced by low KCNA5 expression alone, pointing to an effect specific to the mutant protein. The computational results emphasize that KCNA5 is under mutational selection in colorectal adenocarcinoma, and these mutations are likely functional and contribute to phenotypic alterations in tumors.