Molecular architecture of the fungal-specific potassium channel TOK1

In the major human fungal pathogen Candida albicans, potassium (K+)
channels fine-tune ionic balance under stressful environmental conditions,
contributing to colonization of the human host. Two-pore domain, outwardly
rectifying potassium (TOK) channels, uniquely found in fungi, remain
insufficiently characterized despite early evidence implicating them in
diverse intracellular processes essential for cellular growth and
viability, suggesting their potential as antifungal targets. Here, we
describe the first atomic resolution structure of a fungal potassium
channel - TOK1 from C. albicans (CaTOK) - revealing a unique architecture
defined by eight transmembrane helices and a membrane topology distinct
from all other known K⁺ channel classes. The first four transmembrane
helices form a tetraspanin-like bundle – the TOK auxiliary subunit-like
channel (TALC) domain – that can sense external stimuli and has unexpected
structural homology to auxiliary subunits of human neuronal ion channels.
The TOK1 pore features an inner helical gating mechanism with ‘up’ and
‘down’ conformations analogous to those of mammalian dimeric K⁺ channels.
The K+ selectivity filter of CaTOK exhibits atypical ion coordination at
elevated K⁺ concentrations. Finally, a structured cytosolic C-terminal
bundle directly interacts with the TOK1 pore helices and TALC domain,
establishing an intramolecular network likely important for maintaining
overall channel architecture and modulating gating. These findings provide
a structural framework for understanding TOK channel activity and lay the
groundwork for future studies on fungal ion homeostasis, pathogenicity,
and therapeutic development.