Ion channels and bacterial infection: the case of β‐barrel pore‐forming protein toxins of Staphylococcus aureus

Abstract

Staphylococcus aureus strains causing human pathologies produce several toxins, including a pore-forming protein family formed by the single-component K K-hemolysin and the bicomponent leukocidins and Q Q-hemolysins. The last comprise two protein elements, S and F, that co-operatively form the active toxin. K K-Hemolysin is always expressed by S. aureus strains, whereas bicomponent leukotoxins are more speci¢cally involved in a few diseases. X-ray crystallography of the K K-hemolysin pore has shown it is a mushroom-shaped, hollow heptamer, almost entirely consisting of L L-structure. Monomeric F subunits have a very similar core structure, except for the transmembrane stem domain which has to refold during pore formation. Large deletions in this domain abolished activity, whereas shorter deletions sometimes improved it, possibly by removing some of the interactions stabilizing the folded structure. Even before stem extension is completed, the formation of an oligomeric pre-pore can trigger Ca 2+ -mediated activation of some white cells, initiating an in£ammatory response. Within the bicomponent toxins, Q Q-hemolysins de¢ne three proteins (HlgA, HlgB, HlgC) that can generate two toxins: HlgA+HlgB and HlgC+HlgB. Like K K-hemolysin they form pores in planar bilayers with similar conductance, but opposite selectivity (cation instead of anion) for the presence of negative charges in the ion pathway. Q Q-Hemolysin pores seem to be organized as K K-hemolysin, but should contain an even number of each component, alternating in a 1:1 stoichiometry.

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

“…This is not surprising, because LukS-PV and HlgC have 81% protein sequence identity and most probably share the same epitope recognized by 3A11 HCAb. This result is also in agreement with the report that LukS-PV and HglC compete for the same binding site, whereas HlgA and LukE do not (34). LukS-PV and HlgC also share Trp 275 , an amino acid residue essential for HlgC binding to monosialoganglioside on the leukocyte membrane (35).…”

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

“…Thus, HlgAB and HlgCB share an F subunit. It is worth noting that the gamma-hemolysin subunits are not uniformly named in the literature, which is presumably a consequence of their identification in the pregenomic era but also may have been influenced by the presence of sequence variants isolated from the different S. aureus strains used in a variety of studies (90,(99)(100)(101)(102)(103). This has led to considerable confusion when interpreting studies of gammahemolysin from the late 1980s through the early 1990s.…”

“…In the 10 years following this early assessment of the leucocidin pore, a number of studies using gamma-hemolysin and PVL served to dramatically increase our understanding of the molecular characteristics of pore formation. This work has already been summarized extensively in a series of technical reviews (for details, see references [99][100][101][102]. Notably, substantial biophysical measures of leucocidin pore formation and structural assembly on host cells were performed (156)(157)(158)(159).…”

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

“…SaeRS regulates transcription of multiple toxins, including γ-toxin (hlgA, hlgB, hlgC), LukSF-PVL, and LukAB/LukGH, which have been shown to contribute to PMN lysis (26)(27)(28)(29)(30)(31). Additionally, transcription of the saePQRS operon and SaeR target genes are activated in response to PMN phagocytosis and PMN components (32)(33)(34).…”