Structural Insights Into Shigella Virulence Factor

In 2006, the VirA virulence factor for the pathogenic bacterium Shigella flexneri was identified via biochemical assays as a protease that degrades microtubules in cells (Science 2006, 314, 985). Two independent groups now report X-ray crystal structures that suggest VirA neither functions as a protease nor degrades microtubules. Both the 2.4-Å structure by Benjamin W. Spiller and coworkers of Vanderbilt University Medical Center (Biochemistry, DOI: 10.1021/bi801533k) and the 3.0-Å structure by Alexander Wlodawer and coworkers of the National Cancer Institute's Macromolecular Crystallography Laboratory (Protein Sci., DOI: 10.1110/ps.037978.108) show that VirA is V-shaped with a prominent cleft between the N- and C-terminal domains. VirA had been thought to be similar to papain, a cysteine protease found in papaya, but the structures indicate that VirA lacks homology with papain or any other known protease. In biochemical assays by both teams, purified VirA alone is unable to cleave tubulin. Both teams suggest that VirA may act as a scaffold for an as-yet-undetected cellular factor, perhaps even a cysteine protease.