Biochemistry

Of Bile and Choler

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Science  26 Feb 2010:
Vol. 327, Issue 5969, pp. 1060
DOI: 10.1126/science.327.5969.1060-d
CREDIT: LOWDEN ET AL., PROC. NATL. ACAD. SCI. U.S.A. 107, 10.1073/PNAS.0915021107 (2010)

Vibrio cholerae is the Gram-negative bacterium that causes cholera, a disease that afflicts multitudes of people who lack access to a source of disinfected drinking water. When the bacterium enters the host's intestine, the master virulence regulator ToxT activates the expression of other virulence factors and cholera toxin. ToxT is a member of the AraC family of transcription factors; some of these regulate carbon metabolism (AraC) as dimers, whereas the stress response regulators (SoxS, Rob, and MarA) act as monomers. The promoters to which ToxT binds can be found singly and as inverted repeats. Lowden et al. have solved the ToxT crystal structure. It has an N-terminal regulatory domain and a C-terminal DNA binding domain that shares structural features with AraC, MarA, and Rob. ToxT is a monomer in the crystal, but helix α3 is analogous to the helix that mediates coiled-coil dimerization in AraC. The N-terminal domain contains a hydrophobic pocket that in the crystal is occupied by cis-palmitoleate (slate blue), and the activity of ToxT is known to be inhibited by components of bile. Palmitoleate binds to a lysine residue in the C-terminal domain and locks ToxT into a closed conformation that is not oriented to bind DNA and would also prevent dimerization. This conformation probably occurs in the lumen of the intestine where bile acids are present, yet in the mucus of the intestine, ToxT might be able to reorient into a conformation that can bind DNA and dimerize.

Proc. Natl. Acad. Sci. U.S.A. 107, 2860 (2010).

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