Structure-Function Analysis of Heterodimer Formation, Oligomerization, and Receptor Binding of the Staphylococcus aureus Bi-component Toxin LukGH

Abstract

Background:LukGH is a member of the family of two-component bacterial toxins of Staphylococcus aureus that lyse human phagocytic cells. Results:The crystal structure of LukGH and mutagenesis revealed the molecular basis for heterodimer formation in solution. Conclusion:LukGH differs from other two-component leukocidins that interact only upon cell contact. Significance:These data might assist with development of therapeutics that counteract Staphylococcus aureus pathogenesis.

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

“…It appears that LukAB dimerization occurs prior to secretion, since its toxic potency is highest when the subunits are co-expressed relative to a mixture of individually purified subunits [55, 95]. The lukAB gene is highly polymorphic, with only 82–88% identity between the most divergent strains.…”

“…The lukAB gene is highly polymorphic, with only 82–88% identity between the most divergent strains. In comparison, other leukocidin genes differ by less than 5% between strains, and lukE and lukF-pvl share 82% identity [95]. Despite this diversity, LukAB pairs still exhibit similar abilities to lyse human PMN [95], though it remains to be seen if the polymorphisms in lukAB affect infection in non-human species.…”

The staphylococcal alpha-toxin and leukotoxins

“…Genetic diversity may affect this gene. The structure of this toxin reveals N-and C-terminal extensions in its sequence, but the overall 3D-structure remains conserved compared to the sum of data previously acquired for members of this subfamily of toxins [157]. LukA-LukB heterodimers can be recovered from solution, despite the fact that the toxin seems to be associated with the bacterial surfaces, but Kd for the heterodimer formation remains to be established.…”

“…There is only limited sequence identity (<25%) between S and F proteins and α-toxin, albeit they have homologous each other. However, central domains forming the pore are much more conserved, as well as in other PFTs; i.e., an alternation of hydrophilic versus hydrophobic amino acids ( Figure 25 [21]; LukF-PV-like (Q53704) [161]; LukD (O54082) [143]; LukF-I from Staphylococcus intermedius (Q54327) [166]; HlgB (P0A077) [21]; lukG (T1XT01) [157]; cytK from Bacillus cereus (CAC08441.1) [103]; HlyII from Bacillus cereus (Q63B58) [279]; Hla (P09616) [22]; LukE (O54081) [143]; LukM (Q53703) [161]; LukS-I from Staphylococcus intermedius (Q54326) [166]; LukS-PV (Q2FGU9) [21]; HlgC (Q07227); HlgA (P0A074) [21]; LukH (T1XRZ3) [157]; cpb from Clostridium perfringens (Q46181) [280]; NetB from Clostridium perfringens (4H56) [281]; δ-toxin from Clostridium perfringens (PDB code: 2YGT_A) [282]; PA from Bacillus anthracis (P13423) [283]; Aerolysin from Aeromonas hydrophila (P09167) [284]; α-toxin from Clostridium septicum (Q53482) [285]; Cytotoxin from Pseudomonas aeruginosa (P14608) [286].…”

The role of genetics and antibodies in sepsis

“…Prominent among these targets against S. aureus is alpha toxin and a number of other related two component leukotoxins (57)(58)(59). Other targets are various adhesions and inhibition of biofilm formation (60). Staphylococcal alpha toxin is an attractive target as this is a potent cytotoxin that targets macrophages and impairs phagocytosis.…”