In:
eLife, eLife Sciences Publications, Ltd, Vol. 4 ( 2015-06-02)
Abstract:
The human body is home to many trillions of microbes; most are harmless, but some may cause disease. To live inside a host, microbes must first attach to host tissues. This process involves multiple proteins on each microbe's surface, called adhesins, which interact with the molecules that make up these tissues. Like all proteins, adhesins are long chains of simpler building blocks called amino acids, and each amino acid is connected to the next via a strong ‘covalent’ bond. Adhesins, however, typically attach bacteria to host molecules through the combined strength of many weak ‘non-covalent’ interactions. It was recently discovered that one adhesin from a bacterium called Streptococcus pyogenes contains a rare, extra covalent bond—called a thioester—in an unusual location between two of its amino acids. S. pyogenes is a common cause of throat infections in humans, and can also cause the life-threatening ‘flesh-eating disease’. Walden, Edwards et al. have now used a range of computational, biochemical, structural biology and cell-based techniques to study other adhesins that have thioester bonds in more detail. Computational searches identified hundreds of bacterial proteins containing similar bonds. These included many from bacteria that infect humans: such as Streptococcus pneumoniae, which is the most common cause of pneumonia in adults; and Clostridium difficile, which is notorious for causing severe gut infections in hospital patients. Closer examination of the three-dimensional structures of three of these proteins—including one called SfbI from S. pyogenes—revealed that each had a clear thioester bond. Biochemical tests of an additional nine of the identified proteins strongly suggested they too contained thioester bonds. Walden, Edwards et al. then showed that SfbI was able to not only attach to tissues like conventional adhesins, but also chemically react with fibrinogen: a human protein that is essential for blood clotting and commonly found in inflamed tissues and healing wounds. This chemical reaction results in the formation of a covalent bond between SfbI and fibrinogen, which is as stable as the bonds that link the amino acids in a protein chain. Further experiments revealed that SfbI strongly binds to human cells grown in the lab under conditions that mimic tissue inflammation. Finally, Walden, Edwards et al. made a mutant version of SfbI that did not contain a thioester, and found that it could not interact with fibrinogen nor bind to human cells. Together, these findings suggest that thioesters in bacterial adhesins act like ‘chemical harpoons’, which microbes can use to irreversibly attach themselves to molecules within their host's tissues. This attachment mechanism has not been seen before in host-microbe interactions, and further research is now needed to explore whether interfering with this process could represent a new way to treat bacterial infections.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.06638.001
DOI:
10.7554/eLife.06638.002
DOI:
10.7554/eLife.06638.003
DOI:
10.7554/eLife.06638.004
DOI:
10.7554/eLife.06638.005
DOI:
10.7554/eLife.06638.006
DOI:
10.7554/eLife.06638.007
DOI:
10.7554/eLife.06638.008
DOI:
10.7554/eLife.06638.009
DOI:
10.7554/eLife.06638.010
DOI:
10.7554/eLife.06638.011
DOI:
10.7554/eLife.06638.012
DOI:
10.7554/eLife.06638.013
DOI:
10.7554/eLife.06638.014
DOI:
10.7554/eLife.06638.015
DOI:
10.7554/eLife.06638.016
DOI:
10.7554/eLife.06638.017
DOI:
10.7554/eLife.06638.018
DOI:
10.7554/eLife.06638.019
DOI:
10.7554/eLife.06638.020
DOI:
10.7554/eLife.06638.021
DOI:
10.7554/eLife.06638.022
DOI:
10.7554/eLife.06638.023
DOI:
10.7554/eLife.06638.024
DOI:
10.7554/eLife.06638.025
DOI:
10.7554/eLife.06638.026
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2015
detail.hit.zdb_id:
2687154-3
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