The delivery of a bacterial oncoprotein
Helicobacter pylori infections cause gastric inflammation and increase the risk of stomach cancer. The molecular structure of the factor responsible for the bacterium’s pathogenic action has now been elucidated, opening the route to new therapies.
Photo: Yutaka Tsutsumi
Helicobacter pylori is a bacterial pathogen that infects the mucus layer and the cells that form the inner lining of the stomach. Infection usually provokes an inflammatory reaction that is often without obvious symptoms, although it may sometimes result in a painful bout of gastritis. Infection normally occurs during childhood, and up to 20% of chronically infected patients suffer from recurrent ulcers in the stomach wall or the duodenum. These conditions may in turn develop into full-blown tumors.
A bacterial syringe
Helicobacter pylori was officially designated as an oncogenic (cancer-causing) bacterium in 1994. However, different strains of the pathogen vary markedly in their virulence, which depends on a set of genes named cag that code for a so-called Type IV secretion system. “This molecular complex is found only in strains that are highly pathogenic,” says Professor Rainer Haas. Together with colleagues in France and Belgium, Haas has recently studied the Cag system in detail. “Basically the system works as a molecular syringe, with which the bacterium injects a toxin into the cells of its host.”
The toxic substance is the protein CagA, which promotes the development of tumors by disrupting intracellular signaling pathways. In collaboration with structural biologist Dr. Laurent Terradot and his group at the University of Lyon, Haas and his team have determined the spatial conformation of a large portion of this “bacterial oncoprotein. They found that CagA is made up of a combination of folds that has not been seen in any other protein whose three-dimensional structure has been elucidated, and thus belongs to a previously unknown structural class.
The critical interaction
“We in Munich then took a closer look at how CagA interacts with its receptor on the host cell, focusing on the region of the protein that binds to this receptor,” Haas continues. The results revealed that binding of CagA to an integrin protein on the host-cell surface is essential for injection of the oncoprotein into the cell. The question now is whether this critical interaction can be therapeutically exploited to disrupt or prevent entry of CagA.
“In fact, we were able to show that a fragment of CagA, only 100 amino acids long, is sufficient to block injection of the toxin, at least in cell culture,” Haas explains. This peptide is derived from the binding region of CagA and, given the protein’s unique structure, the fragment may well be able to block the injection of the full-length protein in a highly specific fashion, thus preventing chronic infection, and inhibiting the development of gastric cancer. Haas and his team now intend to study the injection mechanism itself in greater detail. (PNAS online, 20. August 2012) suwe