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Researchers at McMaster University have discovered a molecular "barcode" system that pathogenic bacteria use to distinguish between beneficial and toxic molecules.
The new study, published in the Proceedings of the National Academy of Sciences (PNAS), shows that many bacteria can symbolically scan the genetic code to understand which proteins are retained and which are excreted into the environment.
According to the researchers, those proteins that are excreted are often toxic to human cells, which makes the ability to distinguish proteins critical to the bacteria's ability to cause infectious diseases.
Protein is one of the fundamental building blocks of life," explains John Whitney, associate professor in the McMaster Department of Biochemistry and Biomedical Sciences and principal investigator of the study. "Literally, they allow bacterial pathogens to do everything they do. While the vast majority of proteins remain inside bacteria to perform functions such as metabolism, there are a small percentage of proteins that function outside of the organism, just like toxins.
Michael G. DeGroot Institute for Infectious Diseases (Michael G. G.)Whitney, a member of the Degroote Institute for Infectious Disease Research, said that although the bacterial secretory system and the toxin itself have long been studied, before the study, it was not understood how bacteria distinguish between toxic and non-toxic proteins.
Whitney's lab, led by biochemistry graduate students Prakhar Shah and Timothy Klein (now postdoctoral fellows at the University of California, San Francisco), questioned how three fundamentally different toxins could be secreted by the same bacterial secretion system.
There are no known similarities between these toxins — they don't look like they have any similarities and they don't do anything similar," Whitney said. "Our rationale is that for them all to pass through the same protein secretion machine, they have to have something in common.
Sure enough, there was. Each toxin has a common "domain" that Whitney colloquially likens to a barcode. He said that while all three toxins studied shared a barcode, there was no barcode in the other 3,000 or so proteins in the bacteria, suggesting that it acted as an output signal.
Shah, who is a co-author of the study, said the team was able to prove the concept experimentally through a combination of genetic, biochemical and structural methods, including important "X-ray crystallography studies" that allowed them to purify proteins and gain a clearer understanding of so-called barcodes and their functions.
The research team believes that this new information may eventually lead to a range of important biotechnology and infectious disease-related applications. In particular, Shah noted that the findings are relevant to our understanding of a range of gram-positive pathogens, including the bacterial species that cause serious infectious diseases such as tuberculosis and listeriosis.
A lot of pathogens use this system," Shah said. "Therefore, our findings have important implications for our understanding of the virulence strategies used by multiple human pathogens.
More information: Structure of a tripartite protein complex that targets toxins to the type VII secretion system, Proceedings of the National Academy of Sciences of the United States of America (2024). doi： 10.1073/pnas.2312455121.doi.org/10.1073/pnas.2312455121