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The molecular basis of pH sensing by the human fungal pathogen Candida albicans TOK potassium channel

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Sep 24, 2024 version files 254.52 MB

Abstract

Two-pore domain, outwardly rectifying potassium (TOK) channels are exclusively expressed in fungi, with no homologs in humans, animals, plants, or insects. Recently, TOK channels have been cloned and characterized from several human fungal pathogens and have been posited as potential antifungal targets. TOK channel regulation by drugs and environmental factors is poorly understood. Here, we discovered that Candida albicans TOK (CaTOK) is regulated by extracellular pH, while TOK channels from other fungal species tested are relatively pH-insensitive. Low pH potentiated CaTOK channel outward currents (pKa = 6.0), hyperpolarized the voltage-dependence of activation by -31 mV, and increased pore selectivity for K+ over Na+, shifting the reversal potential (EREV) towards EK. Mutating H144 in the S1-S2 extracellular linker partially diminished pH sensitivity, suggesting H144 forms part of the CaTOK pH sensor. Functional analysis of chimeras with pH-insensitive Saccharomyces cerevisiae TOK and point mutants revealed that V462 and S466 in the final transmembrane segment complete the CaTOK pH-responsive elements. A tripartite network of residues thus endows CaTOK with the ability to functionally respond to pH.