Potassium (K + ) channels play a vital role in helping fungal pathogens like Candida albicans adapt to hostile environments within the human body, including during infection. Among these, two-pore domain, outwardly rectifying K + (TOK) channels, unique to fungi, have remained insufficiently characterized, despite evidence that they support processes in fungi, such as ion homeostasis, growth, and virulence, highlighting their potential as antifungal targets. Here, we present the cryo-EM structure of C. albicans TOK1 (CaTOK), the first resolved structure of a TOK channel and of any fungal K + channel. CaTOK reveals an eight-transmembrane helical fold unlike any other K + channel structure determined to date, including a domain formed by helices S1-S4 with unexpected structural homology to channel auxiliary subunits critical for human neuronal signaling. Additionally, a unique cytosolic C-terminal domain interfaces with pore-lining helices, suggesting a role in channel regulation. These findings uncover previously unrecognized structural elements that broaden our understanding of K + channel diversity and regulation and provide initial clues into the structural basis for the unique functional attributes of the TOK family.
Durocher et al. (Sun,) studied this question.