α‐Hemolysin, γ‐hemolysin, and leukocidin from Staphylococcus aureus: Distant in sequence but similar in structure

Abstract

a-Hemolysin from Staphylococcus aureus assembles from a water-soluble, monomeric species to a membrane-bound heptamer on the surface of target cells, creating water-filled channels that lead to cell death and lysis. Staphylococcus aureus also produces the y-hemolysin and leukocidin toxins, which function as two component toxins in the disruption and lysis of erythrocytes and leukocytes. Analysis of the aligned sequences of a-hemolysin, y-hemolysin, and leukocidin in the context of the a-hemolysin heptamer structure supports the conclusion that even though the level of sequence identity between a-hemolysin and the y-hemolysin and leukocidin toxins is in the so-called twilight zone, the threedimensional structures of the protomers are probably conserved. By analogy with a-hemolysin, y-hemolysin and leukocidin may also form oligomeric, transmembrane channels in which an antiparallel /?-barrel constitutes the primary membrane-embedded domain.Keywords: a-hemolysin; y-hemolysin; heptameric channels; leukocidin; pore-forming bacterial toxins; Staphylococcus aureus; transmembrane /?-barrel Staphylococcus aureus, one of the most common human pathogens, secretes an arsenal of toxins that include a-hemolysin (aHL; Comparison of the sequences corresponding to the mature aHL, yHL and Luk polypeptides shows that the pairwise sequence identity between aHL and the other toxins ranges from 23% to 32%, using the FASTA alignment program (GCG, 1996). As described previously (Cooney et al., 1993), yHL is more closely related to Luk by primary sequence than aHL is related to yHL and Luk.Indeed, the level of sequence conservation between aHL and the yHL and Luk proteins borders on the so-called twilight zone, indicating that conservation of three-dimensional structure is not unambiguous. Multiple-sequence alignments of aHL and nine representative sequences of y H L and Luk using Clustal W (version 1.6; Thompson et al., 1994), MAP (Huang, 1994), and PIMA (Smith & Smith, 1990, operating from the web site http: //dot.imgen.bcm.tmc.edu:9331/multi-align at Baylor College of Medicine, gave similar results, although there were some specific differences between the alignments (Fig. 2). Relative to the aHL sequence, the sites of variation in the multiple sequence alignments using the three programs were located (1) at the amino terminus;

Induction of Virulence Gene Expression in Staphylococcus aureus by Pulmonary Surfactant

“…Hlg shows hemolytic and cytolytic activities against human monocytes, polymorphonuclear cells, and macrophages (47). Hlg and other related hemolysins are predicted to form transmembrane channel complexes on target cells, and the tertiary structure of the Hlg protomer is similar to those of hemolysin alpha (Hla) and leukocidin (48). Among these hemolysins, S. aureus Hla, Panton-Valentine leukocidin, and hemolysin beta (Hlb) contribute to evoking inflammation and host killing in experimental mammalian pneumonia models (49)(50)(51).…”

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

“…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). Key studies included the determination that leucocidins form an octameric pore arranged as alternating S and F subunits (160)(161)(162)(163) as well as detailed biochemical characterizations of residues required for toxin activity, including sites of phosphorylation (164,165), subunit interactions (166)(167)(168)(169)(170), membrane recognition (171)(172)(173)(174), and prepore-to-pore transition states (175)(176)(177).…”

Anti-Alpha-Hemolysin Monoclonal Antibodies Mediate Protection againstStaphylococcus aureusPneumonia

“…This chromosomally encoded toxin is secreted as a water-soluble monomer by the majority of S. aureus strains (22). Membrane binding of the monomer permits a series of well-defined intermolecular interactions between neighboring monomers, resulting in the formation of a barrel-shaped oligomeric pore that penetrates the membrane (9,13). Residues located at the N terminus of the mature toxin are essential for assembly of the lytic oligomer, as point mutations or truncations within this region disrupt the formation of an active toxin (21,27,28).…”