Identification of a crucial residue required for Staphylococcus aureus LukAB cytotoxicity and receptor recognition
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Author(s)
DuMont, Ashley L
Yoong, Pauline
Liu, Xiang
Day, Christopher J
Chumbler, Nicole M
James, David BA
Alonzo, Francis
Bode, Nadine J
Lacy, D Borden
Jennings, Michael P
Torres, Victor J
Year published
2014
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The bicomponent leukotoxins produced by Staphylococcus aureus kill host immune cells through osmotic lysis by forming ??-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicom- ponent leukotoxin family members exhibit these properties. In this study, we report that leukocidin A/B (LukAB), the most di- vergent member ...
View more >The bicomponent leukotoxins produced by Staphylococcus aureus kill host immune cells through osmotic lysis by forming ??-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicom- ponent leukotoxin family members exhibit these properties. In this study, we report that leukocidin A/B (LukAB), the most di- vergent member of the leukotoxin family, exists as a heterodimer in solution rather than two separate monomeric subunits. No- tably, this property was found to be associated with enhanced toxin activity. LukAB also differs from the other bicomponent leukotoxins in that the S subunit (LukA) contains 33- and 10-amino-acid extensions at the N and C termini, respectively. Trun- cation mutagenesis revealed that deletion of the N terminus resulted in a modest increase in LukAB cytotoxicity, whereas the deletion of the C terminus rendered the toxin inactive. Within the C terminus of LukA, we identified a glutamic acid at position 323 that is critical for LukAB cytotoxicity. Furthermore, we discovered that this residue is conserved and required for the inter- action between LukAB and its cellular target CD11b. Altogether, these findings provide an in-depth analysis of how LukAB tar- gets neutrophils and identify novel targets suitable for the rational design of anti-LukAB inhibitors.
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View more >The bicomponent leukotoxins produced by Staphylococcus aureus kill host immune cells through osmotic lysis by forming ??-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicom- ponent leukotoxin family members exhibit these properties. In this study, we report that leukocidin A/B (LukAB), the most di- vergent member of the leukotoxin family, exists as a heterodimer in solution rather than two separate monomeric subunits. No- tably, this property was found to be associated with enhanced toxin activity. LukAB also differs from the other bicomponent leukotoxins in that the S subunit (LukA) contains 33- and 10-amino-acid extensions at the N and C termini, respectively. Trun- cation mutagenesis revealed that deletion of the N terminus resulted in a modest increase in LukAB cytotoxicity, whereas the deletion of the C terminus rendered the toxin inactive. Within the C terminus of LukA, we identified a glutamic acid at position 323 that is critical for LukAB cytotoxicity. Furthermore, we discovered that this residue is conserved and required for the inter- action between LukAB and its cellular target CD11b. Altogether, these findings provide an in-depth analysis of how LukAB tar- gets neutrophils and identify novel targets suitable for the rational design of anti-LukAB inhibitors.
View less >
Journal Title
Infection and Immunity
Volume
82
Issue
3
Copyright Statement
© 2014 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
Subject
Biological sciences
Agricultural, veterinary and food sciences
Biomedical and clinical sciences
Medical bacteriology
Microbiology
Immunology
Medical microbiology