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Abstract
Formate/nitrite transporters (FNTs) selectively transport monovalent anions and are found in prokaryotes and lower eukaryotes. They play a significant role in bacterial growth and act against the defense mechanism of infected hosts. Because FNTs do not occur in higher animals, they are attractive drug targets for many bacterial diseases. Phylogenetic analysis revealed that they can be classified into eight subgroups, two of which belong to the uncharacterized YfdC-α and YfdC-β groups. Experimentally determined structures of FNTs belonging to different phylogenetic groups adopt the unique aquaporin-like hourglass helical fold. We considered the formate channel from Vibrio cholerae, the hydrosulphide channel from Clostridium difficile, and the uncharacterized channel from Escherichia coli (EcYfdC) to investigate the mechanism of transport and selectivity. Using equilibrium molecular dynamics and umbrella sampling studies, we determined temporal channel radius profiles, permeation events, and potential of mean force profiles of different substrates with the conserved central histidine residue in protonated or neutral form. Unlike the formate channel from V. cholerae and the hydrosulphide channel from C. difficile, molecular dynamics studies showed that the formate substrate was unable to enter the vestibule region of EcYfdC. Absence of a conserved basic residue and presence of acidic residues in the vestibule regions, conserved only in YfdC-α, were found to be responsible for high energy barriers for the anions to enter EcYfdC. Potential of mean force profiles generated for ammonia and ammonium ion revealed that EcYfdC can transport neutral solutes and could possibly be involved in the transport of cations analogous to the mechanism proposed for ammonium transporters. Although YfdC members belong to the FNT family, our studies strongly suggest that EcYfdC is not an anion channel. Absence or presence of specific charged residues at particular positions makes EcYfdC selective for neutral or possibly cationic substrates. Further experimental studies are needed to get a definitive answer to the question of the substrate selectivity of EcYfdC. This provides an example of membrane proteins from the same family transporting substrates of different chemical nature.
Highlights
The family of formate/nitrite transporters (FNTs) is selective for monovalent anions, and members of this family are involved in the transport of anions such as formate, nitrite, hydrogen sulphide, and lactate [1,2,3,4,5,6,7,8]
Each Formate/nitrite transporters (FNTs) member was simulated in the presence of the substrates formate or formic acid, and we have considered the highly invariant central His residue (His-209 in PDB: 3KCU numbering) in either the protonated or neutral state (Table 1)
In a recent bioinformatics analysis of FNT family members, 27% of the identified FNTs were classified as members belonging to the YfdC subfamily, and they were further subdivided into two groups, YfdC-a and YfdC-b
Summary
The family of formate/nitrite transporters (FNTs) is selective for monovalent anions, and members of this family are involved in the transport of anions such as formate, nitrite, hydrogen sulphide, and lactate [1,2,3,4,5,6,7,8]. Three-dimensional structures of a few FNT family members representing different subgroups have been determined This includes formate-specific FocA [11,12], nitrite-transporting NirC [4], and hydrogensulphide-selective HSC channels [7]. The selectivity and transport mechanism of FNT members have been investigated by both experimental and computational techniques
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