Abstract
TOKs are outwardly rectifying K+ channels in fungi with two pore-loops and eight transmembrane spans. Here, we describe the TOKs from four pathogens that cause the majority of life-threatening fungal infections in humans. These TOKs pass large currents only in the outward direction like the canonical isolate from Saccharomyces cerevisiae (ScTOK), and distinct from other K+ channels. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K+ -selective and pass current above the K+ reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K+ and Na+ and conduct above a reversal potential reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K+ channels are shown to produce inward TOK currents. A favored model for outward rectification is proposed whereby the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane.
Highlights
Potassium (K+) channels are found across the kingdoms of life and are characterized by their structures and functions
Based on a predicted structure of two pore-forming domains in one subunit (2P), we identified genes encoding K+ channel subunits with four transmembrane spans in animals (2P/4TM or two-pore potassium (K2P)) and a two-pore domain (2P)/8TM subunit in Saccharomyces cerevisiae, ScTOK1 (Figure 1A)
Seeking homologs for comparative studies, and appreciating that the most frequent life-threatening fungal infections are caused in patients with immunological impairment by the genera Candida, Cryptococcus, and Aspergillus,[21] we searched databases using ScTOK as bait, cloned and studied four 2P/8TM this study of fungal K2P (TOK) homologues from the pathogens that operate as ion channels and a 2P/7TM subunit that does not
Summary
HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS), Grant/Award Number: RO1NS58505; HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI), Grant/Award Number: RO1HL61657; Biotechnology and Biological Sciences Research Council, Grant/Award Number: BB/J006114/1; HHS NIH National Institute of General Medical Sciences (NIGMS), Grant/Award Number: RO1GM097159
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