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Unlatching of the stem domains in the Staphylococcus aureus pore-forming leukocidin LukAB influences toxin oligomerization.
Ilmain, Juliana K; Perelman, Sofya S; Panepinto, Maria C; Irnov, Irnov; Coudray, Nicolas; Samhadaneh, Nora; Pironti, Alejandro; Ueberheide, Beatrix; Ekiert, Damian C; Bhabha, Gira; Torres, Victor J.
Affiliation
  • Ilmain JK; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA.
  • Perelman SS; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA.
  • Panepinto MC; Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, New York, USA.
  • Irnov I; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA.
  • Coudray N; Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, New York, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA.
  • Samhadaneh N; Antimicrobial-Resistant Pathogens Program, New York University Langone Health, New York, New York, USA.
  • Pironti A; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA; Antimicrobial-Resistant Pathogens Program, New York University Langone Health, New York, New York, USA.
  • Ueberheide B; Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, New York, USA; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, New York, USA; Department of Neurology, Cente
  • Ekiert DC; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA; Antimicrobial-Resistant Pathogens Program, New York University Langone Health, New York, New Yor
  • Bhabha G; Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA; Antimicrobial-Resistant Pathogens Program, New York University Langone Health, New York, New York, USA.
  • Torres VJ; Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, Tennessee, USA. Electronic address: victor.torres@stjude.org.
J Biol Chem ; 299(12): 105321, 2023 Dec.
Article de En | MEDLINE | ID: mdl-37802313
ABSTRACT
Staphylococcus aureus (S. aureus) is a serious global pathogen that causes a diverse range of invasive diseases. S. aureus utilizes a family of pore-forming toxins, known as bi-component leukocidins, to evade the host immune response and promote infection. Among these is LukAB (leukocidin A/leukocidin B), a toxin that assembles into an octameric ß-barrel pore in the target cell membrane, resulting in host cell death. The established cellular receptor for LukAB is CD11b of the Mac-1 complex. Here, we show that hydrogen voltage-gated channel 1 is also required for the cytotoxicity of all major LukAB variants. We demonstrate that while each receptor is sufficient to recruit LukAB to the plasma membrane, both receptors are required for maximal lytic activity. Why LukAB requires two receptors, and how each of these receptors contributes to pore-formation remains unknown. To begin to resolve this, we performed an alanine scanning mutagenesis screen to identify mutations that allow LukAB to maintain cytotoxicity without CD11b. We discovered 30 mutations primarily localized in the stem domains of LukA and LukB that enable LukAB to exhibit full cytotoxicity in the absence of CD11b. Using crosslinking, electron microscopy, and hydroxyl radical protein footprinting, we show these mutations increase the solvent accessibility of the stem domain, priming LukAB for oligomerization. Together, our data support a model in which CD11b binding unlatches the membrane penetrating stem domains of LukAB, and this change in flexibility promotes toxin oligomerization.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Staphylococcus aureus / Protéines bactériennes / Toxines biologiques / Leucocidine Limites: Animals / Humans Langue: En Journal: J Biol Chem Année: 2023 Type de document: Article Pays d'affiliation: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Staphylococcus aureus / Protéines bactériennes / Toxines biologiques / Leucocidine Limites: Animals / Humans Langue: En Journal: J Biol Chem Année: 2023 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
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