Structural basis for virulence regulation in Vibrio cholerae by unsaturated fatty acid components of bile

Cruite, Justin T.; Kovacikova, Gabriela; Clark, Kenzie A.; Woodbrey, Anne K.; Skorupski, Karen; Kull, F. Jon

doi:10.1038/s42003-019-0686-x

Structural basis for virulence regulation in Vibrio cholerae by unsaturated fatty acid components of bile

Journal Article · Wed Nov 27 23:00:00 EST 2019 · Communications Biology

DOI:https://doi.org/10.1038/s42003-019-0686-x· OSTI ID:1624534

Cruite, Justin T. ^[1]; Kovacikova, Gabriela ^[2]; ^[3]; Woodbrey, Anne K. ^[4]; Skorupski, Karen ^[2]; Kull, F. Jon ^[5]

Geisel School of Medicine at Dartmouth College, Hanover, NH (United States). Department of Biochemistry and Cell Biology; Dartmouth College; Guarini School of Graduate and Advanced Studies, Hanover, NH (United States).; DOE/OSTI
Geisel School of Medicine at Dartmouth College, Hanover, NH (United States). Department of Microbiology and Immunology
Dartmouth College, Hanover, NH (United States). Dept. of Chemistry
Dartmouth College; Guarini School of Graduate and Advanced Studies, Hanover, NH (United States); Dartmouth College, Hanover, NH (United States). Dept. of Chemistry
Geisel School of Medicine at Dartmouth College, Hanover, NH (United States). Department of Biochemistry and Cell Biology; Dartmouth College; Guarini School of Graduate and Advanced Studies, Hanover, NH (United States); Dartmouth College, Hanover, NH (United States). Dept. of Chemistry

The AraC/XylS-family transcriptional regulator ToxT is the master virulence activator of Vibrio cholerae, the gram-negative bacterial pathogen that causes the diarrheal disease cholera. Unsaturated fatty acids (UFAs) found in bile inhibit the activity of ToxT. Crystal structures of inhibited ToxT bound to UFA or synthetic inhibitors have been reported, but no structure of ToxT in an active conformation had been determined. Here we present the 2.5 Å structure of ToxT without an inhibitor. The structure suggests release of UFA or inhibitor leads to an increase in flexibility, allowing ToxT to adopt an active conformation that is able to dimerize and bind DNA. Small-angle X-ray scattering was used to validate a structural model of an open ToxT dimer bound to the cholera toxin promoter. The results presented here provide a detailed structural mechanism for virulence gene regulation in V. cholerae by the UFA components of bile and other synthetic ToxT inhibitors.

View Accepted Manuscript (DOE)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624534

Alternate ID(s):: OSTI ID: 1690163

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 2; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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