Staphylococcus aureus Exfoliative Toxin E, Oligomeric State and Flip of P186: Implications for Its Action Mechanism

Staphylococcal exfoliative toxins (ETs) are glutamyl endopeptidases that specifically cleave the Glu381-Gly382 bond in the ectodomains of desmoglein 1 (Dsg1) via complex action mechanisms. To date, four ETs have been identified in different Staphylococcus aureus strains and ETE is the most recently...

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Published in:International journal of molecular sciences 2022-09, Vol.23 (17), p.9857
Main Authors: Gismene, Carolina, Hernández González, Jorge Enrique, Santisteban, Angela Rocio Niño, Ziem Nascimento, Andrey Fabricio, dos Santos Cunha, Lucas, de Moraes, Fábio Rogério, de Oliveira, Cristiano Luis Pinto, Oliveira, Caio C., Jocelan Scarin Provazzi, Paola, Pascutti, Pedro Geraldo, Arni, Raghuvir Krishnaswamy, Barros Mariutti, Ricardo
Format: Article
Language:English
Subjects:
Carbonyls
Crystal structure
Desmoglein 1
Enzymatic activity
Epidemics
Free energy
Occlusion
Peptides
Proteins
Skin
Staphylococcus aureus
Toxins
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Summary:Staphylococcal exfoliative toxins (ETs) are glutamyl endopeptidases that specifically cleave the Glu381-Gly382 bond in the ectodomains of desmoglein 1 (Dsg1) via complex action mechanisms. To date, four ETs have been identified in different Staphylococcus aureus strains and ETE is the most recently characterized. The unusual properties of ETs have been attributed to a unique structural feature, i.e., the 180° flip of the carbonyl oxygen (O) of the nonconserved residue 192/186 (ETA/ETE numbering), not conducive to the oxyanion hole formation. We report the crystal structure of ETE determined at 1.61 Å resolution, in which P186(O) adopts two conformations displaying a 180° rotation. This finding, together with free energy calculations, supports the existence of a dynamic transition between the conformations under the tested conditions. Moreover, enzymatic assays showed no significant differences in the esterolytic efficiency of ETE and ETE/P186G, a mutant predicted to possess a functional oxyanion hole, thus downplaying the influence of the flip on the activity. Finally, we observed the formation of ETE homodimers in solution and the predicted homodimeric structure revealed the participation of a characteristic nonconserved loop in the interface and the partial occlusion of the protein active site, suggesting that monomerization is required for enzymatic activity.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23179857