Necrotic activity of ExhC from Mammaliicoccus sciuri is mediated by specific amino acid residues

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Gismene, Carolina ; Gonzalez, Jorge Enrique Hernandez ; Calmon, Marilia de Freitas ; Nascimento, Andrey Fabricio Ziem ; Santisteban, Angela Rocio Nino ; Calil, Felipe Antunes ; da Silva, Alana Della Torre ; Rahal, Paula ; Goes, Rejane Maira ; Arni, Raghuvir Krishnaswamy ; Mariutti, Ricardo Barros

• Document type: Journal article
• Source: International Journal of Biological Macromolecules; v. 254, p. 11-pg., 2023-11-08.

Abstract

Mammaliicoccus sciuri, a commensal and pathogenic bacterium of significant clinical and veterinary relevance, expresses exfoliative toxin C (ExhC), a specific glutamyl endopeptidase belonging to the chymotrypsin family as the principal virulence factor. However, unlike most members of this family, ETs are inactive against a wide range of substrates and possess exquisite specificity for desmoglein-1 (Dsg1), a cadherin-like adhesion molecule that is crucial to maintain tissue integrity, thereby preventing the separation of skin cells and the entry of pathogens. ExhC is of clinical importance since in addition to causing exfoliation in pigs and mice, it induces necrosis in multiple mammalian cell lines, a property not observed for other ETs. Previous experiments have implicated the ExhC79-128 fragment in causing necrosis. Site-directed mutagenesis of specific residues within this fragment were studied and led to the design of an ExhC variant containing four-point mutations (ExhCmut4) lacking necrotic potential but retaining nearly wild-type (wt) levels of enzymatic activity. Moreover, the determination of the ExhCwt and ExhCmut4 crystal structures identified the conformation in the necrosis-linked region. These results constitute an important step toward the understanding of the mechanisms underlying the necrotic and epidermolytic activity of ExhC. (AU)

• FAPESP's process: 20/10214-1 - Integrated computational and experimental strategies for the inhibition of exfoliative toxins from Staphylococcus aureus
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/08615-8 - Protein exosites, cryptic sites and moonlighting: identification, functional mapping and effects of changes in structure
• Grantee: Raghuvir Krishnaswamy Arni
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/13921-0 - Structural determinants of necrotic and epidermolytic activity of exfoliative protein C (ExhC) of Staphylococcus sciuri
• Grantee: Carolina Gismene
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/10941-6 - Identification of potential inhibitors of necrotic and epidermolytic activity of exfoliative toxin C from Staphylococcus sciuri through secondary sites mapping
• Grantee: Carolina Gismene
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 19/10230-0 - Determinants of the necrotic activity of exfoliative protein C (ExhC) from Staphylococcus sciuri
• Grantee: Carolina Gismene
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 22/14362-0 - Protein exosites, cryptic sites and moonlighting: Identification, functional mapping and effects of changes in structure
• Grantee: Felipe Antunes Calil
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/03901-8 - Computer-guided identification of inhibitors against staphylococcal exfoliative toxins
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor