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HZI researchers use cryo-electron microscopy to visualize important bacterial transport channel
Most bacteria, including many bacterial pathogens, are surrounded by an outer protective layer of sugar molecules, known as a capsule. This primarily protects the bacteria from environmental influences, but also serves as a kind of cloak of invisibility, enabling them to evade the phagocytes of our immune system. Structural biologists at the Helmholtz Centre for Infection Research (HZI) have now used cryo-electron microscopy to visualize the central Wza-Wzc protein complex, with which sugar molecules pass from the interior of the bacterial cell to the outside, in three dimensions at the atomic level for the first time. Their investigations also show how the channel is formed and which molecular players are involved in the active transport of sugar molecules through the channel. The researchers hope that their study will help identify target structures for potential drugs that could inhibit or completely prevent the formation of the bacterial capsule in the future. This would also make such bacterial pathogens vulnerable to attack by the immune system. The study was conducted in collaboration with researchers from the Centre for Structural Systems Biology (CSSB) in Hamburg and has now been published in the journal Nature Communications.
“Many bacteria are not naked, but rather well-packaged – with a protective shell made of a dense network of sugar molecules that protects them from external environmental influences such as dehydration,” says Prof. Dirk Heinz, head of the department “Molecular Structural Biology” at the HZI. "This capsule has another advantage for bacterial pathogens: It acts as a cloak of invisibility. This is because the highly variable interlinked sugar molecules of the bacterial capsule make it difficult for our immune cells to recognize them."
Against the backdrop of increasing antibiotic resistance, the HZI is also working intensively on researching new active substances against bacterial pathogens. What if we knew more about how and where the sugar cloak of bacteria is knitted? “That would be an ideal starting point for developing active substances that could prevent or at least curb the formation of the bacterial capsule. This would reveal the underlying structures of the bacterium, which our immune cells could then attack more effectively,” explains Dr Biao Yuan, a scientist in Dirk Heinz's HZI research group and first author of the study.
It is known that a protein complex called Wza-Wzc plays a key role in the production of the capsule in so-called Gram-negative bacteria, which include many pathogens. However, exactly what this complex looks like and how the sugar molecules are transported from the interior of the bacterium to the outside was previously unclear. Now, the HZI structural biologists have been able to shed light on this with their study.
For their research, the scientists used so-called cryo-electron microscopy. This technique allows real images of the three-dimensional structure of proteins to be created at high spatial resolution. They conducted their investigations on the bacterium Escherichia coli K-12, a non-pathogenic laboratory strain of the intestinal bacterium E. coli, which belongs to the Gram-negative bacteria. Gram-negative bacteria have a cell membrane that surrounds the cell interior and an additional outer membrane above it. On the very outside is the protective bacterial capsule made of sugar molecules, which is closely connected to the outer membrane. The sugar molecules formed inside the cell must therefore somehow pass through the cell membrane and outer membrane to make their way out.
“We discovered that the Wzc protein, which is positioned as a ring-shaped octamer within the cell membrane, performs a kind of search movement triggered by a biochemical process. It extends a molecular arm and, in this way, comes into contact with the Wza protein, which also consists of eight units and is located within the outer membrane above,” explains Biao Yuan. “They then form a continuous transport channel through which the sugar molecules, with the help of another protein, Wzy polymerase, pass from the interior of the bacterium to the outside, where they form the capsule.” The bacteria's sugar cloak is thus knitted with the help of the Wza-Wzc-Wzy transport system, which functions like a kind of molecular knitting loom. Inside, the sugar molecules become entangled with each other and come out the other side, where they become part of the cloak of invisibility.
“Our study enabled us to generate real 3D images of the Wza-Wzc transport channel for the first time. We were thus able to conclusively prove its previously postulated existence,” says Dirk Heinz. “In addition, we identified molecular building blocks that are essential for its formation and function.” The researchers also found initial evidence of which molecular players are involved in actively transporting sugar molecules through the channel. In further studies, the research team plans to investigate the Wza-Wzc transport channel and its molecular functional partners in more detail. Their goal is to identify possible target structures for active substances that can be used to deprive the bacteria of their knitting supplies to produce their protective cloak of invisibility.
Text: Nicole Silbermann
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defense mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. https://www.helmholtz-hzi.de/en
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susanne.thiele@helmholtz-hzi.de
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Yuan, B., Sieben, C., Raj, P. et al. Molecular insights into the capsular polysaccharide transporter Wza-Wzc complex. Nat Commun 17, 1436 (2026). DOI: 10.1038/s41467-026-69136-2 https://doi.org/10.1038/s41467-026-69136-2
https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/molecular-knit... HZI Press Release
Cross-sectional view of the cryo-EM structure of the Wza–Wzc CPS transporter.
Copyright: HZI/Biao Yuan
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