The protein transports heme molecules through the cell membrane
What looks like a tangle of colorful telephone cables are the 3D structures of bacterial proteins. In order to infect the human host and to survive in humans, they are essential for the bacterium: they help it to breathe and generate energy. The role played by a protein called CydDC was a mystery that occupied researchers from all over the world for decades. Only if they understand the biochemical processes in bacteria can they specifically develop new drugs or improve therapies. Scientists from the Max Planck Institute for Biophysics, Virje University Amsterdam in the Netherlands, the University of Ghent in Belgium and the University of Kent in the United Kingdom have now been able to solve the mystery of CydDC and show that so-called heme molecules are produced by the membrane.
© Dan W. Nowakowski, N MOLECULAR SYSTEMS. Cover Design: Alex Wing. Source: Wu, D., Mehdipour, AR, Finke, F. et al. Dissecting the conformational complexity and mechanism of a bacterial heme transporter. Nat Chem Biol 19, 992-1003 (2023). CydDC (green) sits in the inner membrane of bacteria and transports heme (yellow) laden with iron ions (bright yellow) from the cytoplasm through the membrane to the other side. There the heme molecules can enter the cytochrome vol Oxidase (light purple) to activate cellular respiration, which helps bacteria generate energy and survive in the human host. © Dan W. Nowakowski, N MOLECULAR SYSTEMS. Cover Design: Alex Wing. Source: Wu, D., Mehdipour, AR, Finke, F. et al. Dissecting the conformational complexity and mechanism of a bacterial heme transporter. Nat Chem Biol 19, 992-1003 (2023).
Numerous human diseases are caused by bacteria. Many of them are still fatal today, almost 100 years after the discovery of the first antibiotic penicillin, tuberculosis being the most common. As the number of multi-resistant bacterial strains continues to grow, treating infections with common antibiotics is becoming increasingly difficult. Scientists are therefore researching bacterial molecules in order to identify new targets for drugs.
How do bacteria breathe in the human body?
The research team headed by Schara Safarian at the Max Planck Institute for Biophysics has been investigating the structure and functionality of cytochromes for years vol Oxidases – a class of proteins found in bacteria, including the causative agent of tuberculosis. cytochrome vol Oxidases help the bacterium to breathe in the oxygen-poor environment of the host body. In doing so, they convert oxygen into water to generate energy from nutrients. For this process need cytochrome vol Oxidases so-called heme molecules that can “hold” iron ions. In organisms, these iron ions mediate the transfer of electrons between different molecules and thus help to convert oxygen into water during respiration.
It has been known for decades that cytochrome bd oxidases also need a protein complex called CydDC to function properly. However, the exact role CydDC plays in bacterial energy metabolism has so far remained unclear. Researchers speculated about a wide variety of functions until the team led by Schara Safarian finally cracked the riddle: CydDC is a heme transporter. Like the cytochrome vol Oxidases are located in the inner membrane of bacteria. It transports heme molecules from the cytoplasm through this membrane to the other side like a gate. Only there can the heme molecules enter the framework of the cytochrome vol Oxidases are incorporated and thus activate cell respiration.
“If you could switch off CydDC with drugs, breathing would no longer work and the bacteria could not survive in humans,” explains Di Wu, postdoctoral researcher at the Max Planck Institute for Biophysics and first author of the study. “Because we humans don’t have CydDC in our cells ourselves, it would be a good target for new antibiotics.”
International interdisciplinary cooperation got the project going
The interdisciplinary collaboration of experts from the Max Planck Institute for Biophysics and the Universities of Amsterdam, Ghent and Kent, who combined experimental and computer-based methods, ensured the success in clarifying the function of CydDC. “The CydDC project was a sleeping giant that only woke up when the right team formed around it,” said project leader Safarian.
Sonja Welsch and her team played a large part in the success of the project. She heads the Electron Microscopy Center at the Max Planck Institute for Biophysics and thanks to her many years of experience and her expert knowledge, the researchers were able to visualize the CydDC complexes, which are only a few ten-thousandths of a millimeter in size, in an impressive high-throughput approach with high-resolution electron microscopes in over 20 data sets. Powerful computer simulations then helped to visualize how the CydDC transporters take up and release heme, dynamically changing their structure.