Researchers at Harvard Medical School, the University of California, San Francisco, and the University of Georgia have described how the protein that allows strep and staph bacteria to stick to human cells is prepared and packaged. The research, which could facilitate the development of new antibiotics, will appear in the April 6 issue of the Journal of Biological Chemistry.
All bacteria have a standard secretion system that allows them to export different types of proteins outside of their cells. An important class of extracellular molecules produced by pathogenic bacteria are adhesins, proteins that enable bacteria to adhere to host cells. For unknown reasons, the SRR (serine-rich-repeat) adhesins of Staphylococcus and Streptococcus bacteria - pathogens that can be involved in serious infections such as bacterial meningitis, bacterial pneumonia and pericarditis - are transported through a secretion pathway that is similar to the standard system, but dedicated solely to adhesin.
Pathogenic gram-positive bacteria, such as S. gordonii, export a serine-rich adhesin to facilitate their attachment to host cells. Adhesin uses a dedicated secretion pathway, with several steps occurring in the cytosol before its translocation across the membrane. The adhesin GspB (shown in red) is first modified by N-acetylglucosamine (orange hexagon) and glucose (wheat hexagon) in a strictly sequential order. It is then targeted to the membrane by a complex of three accessory secretion proteins (Asp 1-3; shown in green, blue, and pink), two of which resemble carbohydrate-binding proteins (crystals structures are shown ribbon diagrams imbedded in space-filling presentation). Finally, GspB adhesin is moved through the membrane by a dedicated ATPase (SecA2) and membrane channel (SecY2) (both shown in cyan).
Credit: Yu Chen, Harvard Medical School
It would be as if a warehouse that processes many types of goods were to have a separate set of doors and forklifts for just one of its wares. Tom Rapoport, a professor at Harvard Medical School who oversaw the new study, wanted to understand what exactly these dedicated molecular supply chains were doing.
"I was intrigued by the fact that there is a second secretion system in some bacteria that is separate from the canonical secretion system and is just dedicated to the secretion of one protein," Rapoport said. "There is a whole machinery, and it's only doing one thing."
Yu Chen, at the time a postdoctoral research associate in Rapoport's lab, led the investigation. She found that, in order to be transported, the adhesin protein needed to be modified with specific sugars by three enzymes acting in a specific sequence. These sugar modifications stabilize the protein and enhance its stickiness to target cells.
Furthermore, the experiments showed that two proteins in the adhesin-specific pathway, whose function had previously been mysterious, seemed to be able to bind to these sugars, presumably enabling them to carry the adhesin to the cell membrane where adhesin's dedicated exit channel is located.
The complexity of the adhesin transport system necessitated collaboration with research teams at UCSF, Harvard Medical School, and the University of Georgia. Members of Paul Sullam's lab at UCSF provided the clinical perspective, members of Maofu Liao's lab at Harvard characterized the targeting complex by electron microscopy, and members of Parastoo Azadi's lab at Georgia analyzed the sugar modifications.
"It's a complicated system because it involves protein modification, chaperone activity and membrane targeting, so we encountered a lot of challenges," Chen said. "This (study) is a great example of how collaboration across labs in the scientific community advances human knowledge."
The reason that these bacteria use this separate export pathway for adhesins remains elusive. But because this pathway is unique to strep and staph bacteria, the new understanding of its components could help researchers develop highly targeted antibiotics to treat infections caused by these bacteria in the future.
"You could imagine that you could develop novel antibiotics that could target this pathway," Rapoport said. "(They) would be very specific for pathogenic bacteria."
The work was funded by the National Institutes of Health, the U.S. Department of Energy and the Howard Hughes Medical Institute.
About the Journal of Biological Chemistry
JBC is a weekly peer-reviewed scientific journal that publishes research "motivated by biology, enabled by chemistry" across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.
About the American Society for Biochemistry and Molecular Biology
The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society's student members attend undergraduate or graduate institutions. For more information about ASBMB, visit http://www.
Alexandra Mushegian | EurekAlert!
Study clarifies kinship of important plant group
05.08.2020 | Rheinische Friedrich-Wilhelms-Universität Bonn
Human cell-based test systems for toxicity studies: Ready-to-use Toxicity Assay (hiPSC)
05.08.2020 | Fraunhofer-Institut für Biomedizinische Technik IBMT
An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.
Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...
Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...
“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.
Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...
An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.
Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...
Although no life has been detected on the Martian surface, a new study from astrophysicist and research scientist at the Center for Space Science at NYU Abu...
23.07.2020 | Event News
21.07.2020 | Event News
07.07.2020 | Event News
05.08.2020 | Physics and Astronomy
05.08.2020 | Health and Medicine
05.08.2020 | Earth Sciences