Little, Dustin J., and Brian K. Coombes. "Molecular basis for CesT recognition of type III secretion effectors in enteropathogenic Escherichia coli." PLoS pathogens 14, no. 8 (2018): e1007224. DOI: 10.1371/journal.ppat.1007224
Light source identifies a key protein interaction during E. coli infection
Saskatoon, Sask. – Escherichia coli is a common source for contaminated water and food products, causing the condition known as gastroenteritis with symptoms that include diarrhea, vomiting, fever, loss of energy, and dehydration. In fact, for children or individuals with weakened immune systems, this bacterial infection in the gut can be life-threatening.
One of the microbes responsible for gastroenteritis, known formally as enteropathogenic E. coli (EPEC), causes infections by directing a pointed, needle-like projection into the human intestinal tract, releasing toxins that make people sick.
“Enteropathogenic E. coli can fire toxic proteins from inside the bacterium right into the cells of your gut lining,” says Dustin Little, a post-doctoral researcher in the Brian Coombes lab at McMaster University’s Department of Biochemistry and Biomedical Sciences.
If these EPEC toxins were found within the intestinal tract, they would be quickly identified and removed by immune system cells that are constantly on the lookout for such invaders. However, as these toxins are injected directly into the intestinal cells, they avoid such detection and begin to subvert normal cellular behaviour, which ultimately results in the symptoms of the disease.
The proper delivery of protein toxins to the injection needle calls for a chaperone, an agent that specializes in folding and protecting proteins to achieve specific chemical conformations. In this case, the chaperone recognizes a key toxin called the Translocated Intimin Receptor (Tir), so it goes by the name CesT (for Chaperone of the E. coli-secreted protein Tir).
For Little, CesT has become the target of research aimed at neutralizing the way EPEC causes infections like gastroenteritis.
The Canadian Light Source has made a critical contribution to that goal by enabling Little and his colleagues to sort out the structural details of CesT in complex with Tir.
The resulting high-resolution imagery provided the researchers with some surprises, including where exactly the chaperone binds to the Tir protein. It turns out there is more than one possible point of contact, of which, one is critical for injecting Tir into the host. If Tir cannot enter into the intestinal cells, then the symptoms of an E. coli infection become minimal or absent.
“If we can understand that process,” Little explains, “then we can potentially understand how we might design a drug or antimicrobial peptide that you could use to inhibit that process.
Story by Tim Lougheed
Contact CLS Communications Coordinator Victoria Martinez for interview requests
Dec 21, 2018
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