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• W2948664626 startingPage "931" @default.
• W2948664626 abstract "Abstract Like many Gram‐negative pathogens, Shigella rely on a type three secretion system (T3SS) for injection of effector proteins directly into eukaryotic host cells to initiate and sustain infection. Protein secretion through the needle‐like type three secretion apparatus (T3SA) requires ATP hydrolysis by the T3SS ATPase Spa47, making it a likely target for in vivo regulation of T3SS activity and an attractive target for small molecule therapeutics against shigellosis. Here, we developed a model of an activated Spa47 homo‐hexamer, identifying two distinct regions at each protomer interface that we hypothesized to provide intermolecular interactions supporting Spa47 oligomerization and enzymatic activation. Mutational analysis and a series of high‐resolution crystal structures confirm the importance of these residues, as many of the engineered mutants are unable to form oligomers and efficiently hydrolyze ATP in vitro. Furthermore, in vivo evaluation of Shigella virulence phenotype uncovered a strong correlation between T3SS effector protein secretion, host cell membrane disruption, and cellular invasion by the tested mutant strains, suggesting that perturbation of the identified interfacial residues/interactions influences Spa47 activity through preventing oligomer formation, which in turn regulates Shigella virulence. The most impactful mutations are observed within the conserved Site 2 interface where the native residues support oligomerization and likely contribute to a complex hydrogen bonding network that organizes the active site and supports catalysis. The critical reliance on these conserved residues suggests that aspects of T3SS regulation may also be conserved, providing promise for the development of a cross‐species therapeutic that broadly targets T3SS ATPase oligomerization and activation." @default.
• W2948664626 created "2019-06-14" @default.
• W2948664626 creator A5031081669 @default.
• W2948664626 creator A5041369277 @default.
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• W2948664626 date "2019-06-21" @default.
• W2948664626 modified "2023-10-16" @default.
• W2948664626 title "Interfacial amino acids support Spa47 oligomerization and <i>shigella</i> type three secretion system activation" @default.
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• W2948664626 doi "https://doi.org/10.1002/prot.25754" @default.
• W2948664626 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6779512" @default.
• W2948664626 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31162724" @default.
• W2948664626 hasPublicationYear "2019" @default.
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