Connecting Structural Biology and Wound Healing

How do pathogenic agents actually manage to overcome the defence barriers of the human body and attack the organism? The team around Professor Dr. Dirk Heinz at the Department of Structural Biology of the HZI pursues this question. In doing so, the researchers analyse the structures of so-called virulence factors from pathogenic microorganisms by means of x-ray structural analysis, nuclear magnetic resonance spectroscopy and mass spectrometry. Virulence factors are special proteins produced by pathogens that allow them to invade and spread throughout the host cells. “The structural analysis of proteins involved in the infection process is of special importance to us, since the threedimensional structure of a protein can provide us with information about its actual function”, says Heinz.

Together with his colleagues he studies the virulence factors of a whole range of human pathogenic bacteria, viruses and fungi. These include the bacterial pathogens, for instance, from Listeria that are found in spoiled food and invade the body via the intestinee. To break through the intestinal barrier, the surface protein internalin A of the bacterium serves as a “key”. It interacts with the protein E-cadherin located on human intestinal cells and adheres to the surface. Subsequently, the bacterium can now invade the organism and spread through the body via the bloodstream.

In contrast to humans, mice are not susceptible to Listeria infections via this route. The HZI researchers have found an explanation for this phenomenon by comparative structural analysis of the E-cadherins from humans and mice: The mouse Ecadherin features a slightly different structure to that of human E-cadherin. Hence, internalin A of Listeria cannot interact with mouse E-cadherin, which is why mice are immune against the intestinal infection with Listeria via the oral route.

Since animal models involving mice play a crucial role in medical research, Heinz and his team have successfully modified the internalin A of Listeria in such a way as to enable it to interact with mouse E-cadherin. Since the structure of mouse E-cadherin was already known, the structural biologists succeeded in producing a Listeria strain that was pathogenic to mice by making two mutations in the Listeria genome. “We do not intend to just analyse structures, but also, if possible to generate new functional knowledge. Through structural biology of the internalins we were able to develop a new animal model for humane listeriosis. In the long term, the results of our research create the basis for the development of new active substances and diagnostics”, says Heinz.

By way of a new study, the HZI researchers provide another important example: Internalin B is a second invasion protein of Listeria. It imitates a growth factor and interacts with the human cell surface receptor Met which, amongst other functions, is involved in wound healing processes. The researchers found that two internalin B molecules artificially linked together cause an increased activation of the Met receptor. Heinz: “In this form the dimeric internalin B molecule could also positively influence wound healing processes. These results could be of major significance for medical support during wound healing processes - in particular wounds that do not heal well and require intensive treatment. Thus, coming from infection biology we arrive at wound healing – this, too, is possible with insights from structural biology.”

Heinz is convinced that health research profits from structural biology in many ways. Recently, the Department of Molecular Structural Biology of the HZI has become an associated member in the future Europe-wide research network for integrated structural biology infrastructures (INSTRUCT). As a European centre for protein production, the HZI supplies proteins produced using mammalian and insect cells with new technologies developed within the context of the Helmholtz “Protein Sample Production Facility” platform of the institute. Within the Helmholtz Association the HZI is playing a leading role in a new initiative on the site of the campus of the Deutsches Elektronen-Synchrotron DESY in Hamburg-Bahrenfeld. The Centre for Structural System Biology (CSSB) is to be created there to investigate biological structures at high resolution using extremely powerful photon sources.