Title

Deoxycholate-Enhanced Shigella Virulence Is Regulated by a Rare π-Helix in the Type Three Secretion System Tip Protein IpaD

Document Type

Article

Journal/Book Title

Biochemistry

Publication Date

11-2017

Funder

NIH

Publisher

American Chemical Society

Award Number

NIH 1R15AI124108-01A1

Volume

49

Issue

56

First Page

6503

Last Page

6514

DOI

10.1021/acs.biochem.7b00836

Abstract

Type three secretion systems (T3SS) are specialized nanomachines that support infection by injecting bacterial proteins directly into host cells. The Shigella T3SS has uniquely evolved to sense environmental levels of the bile salt deoxycholate (DOC) and upregulate virulence in response to DOC. In this study, we describe a rare i + 5 hydrogen bonding secondary structure element (π-helix) within the type three secretion system tip protein IpaD that plays a critical role in DOC-enhanced virulence. Specifically, engineered mutations within the π-helix altered the pathogen’s response to DOC, with one mutant construct in particular exhibiting an unprecedented reduction in virulence following DOC exposure. Fluorescence polarization binding assays showed that these altered DOC responses are not the result of differences in affinity between IpaD and DOC, but rather differences in the DOC-dependent T3SS tip maturation resulting from binding of IpaD to translocator/effector protein IpaB. Together, these findings begin to uncover the complex mechanism of DOC-enhanced Shigella virulence while identifying an uncommon structural element that may provide a much needed target for non-antibiotic treatment of Shigella infection.

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