Editors' ChoiceMicrobiology

No Muss, No Fuss: Easy Protein Structure-Function Analysis

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Science Translational Medicine  06 Jan 2010:
Vol. 2, Issue 13, pp. 13ec1
DOI: 10.1126/scitranslmed.3000768

One type of the common bacterium Escherichia coli is especially good at infecting the bladder and causes most urinary tract infections. The key to its skill is a protein called FimH adhesin, which perches at the end of E. coli's pilus, a hairlike structure that projects from surface. Through FimH, the bacterium binds to mannose, a sugar attached to surface proteins on the bladder epithelium, and then enters the epitheliala cells themselves, where it forms biofilm colonies. Chen et al. have now found an easy way to locate the regions of this virulence protein that are critical for its infectiousness by using a maximum-likelihood algorithm to find amino acids under positive selection.

The mannose-binding region of FimH has been well defined. Mutations there render the bacteria unable to infect cells; its eight amino acids were identical in 188 strains that the authors tested, confirming that this part of the protein is essential for its function. The authors used their algorithm to look for amino acids that have been subject to positive selection outside the mannose binding area and found four that met the criteria. Experiments confirmed that the algorithm found some interesting amino acids: Mutation of various combinations of these residues in the bacteria impaired the ability of these E. coli to infect mice, although they could still bind mannose perfectly well. Further work showed that these positively selected amino acids controlled the bacteria's ability to get into the urinary tract's epithelial cells and form aggregates, now known to be a second essential step in infection along with mannose binding.

This in silico approach clarified the dual role of FimH adhesin in pathogenesis: mannose binding and bacterial aggregate formation. And, because DNA sequences are relatively easy to come by and this method was able to identify amino acid residues that were indeed functionally important, this approach may prove to be an important tool for biochemists trying to understand protein structure and function, which is the first step in designing a targeted therapeutic agent.

S. L. Chen et al., Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding. Proc. Natl. Acad. Sci. U.S.A. 106, 22439–22444 (2009). [Full Text]

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