Artificial intelligence detects new gene family in gut bacteria
Using artificial intelligence, UT Southwestern researchers have discovered a new family of sensing genes in enteric bacteria that are linked by structure and likely function, but not by genetic sequence. The findings, published in PNASoffer a new way to identify the role of genes in unrelated species and could lead to new ways to fight intestinal bacterial infections.
“We have identified similarities in these proteins in reverse of how it is usually done. Instead of using the sequence, Lisa looked for matches in their structure,” said Kim Orth, Ph.D., professor of molecular biology and biochemistry, who co-led the study with Lisa Kinch, Ph.D. , specialist in bioinformatics in the Department of Molecular Biology.
Dr. Orth’s lab has long focused on studying how marine and estuarine bacteria cause infections. In 2016, Dr. Orth and colleagues used biophysics to characterize the structure of two proteins called VtrA and VtrC complexes that work in concert in a bacterial species known as Vibrio parahaemolyticus. She and her team then discovered the VtrA/VtrC complex by V. parahaemolyticus – which is often the cause of food poisoning from contaminated shellfish – detects bile on the surface of bacterial cells, sending a signal to initiate a chemical cascade that prompts this microbe to invade the intestinal cells of its human host.
Although VtrA shares some structural features with a protein called ToxR found in a related bacterium called Vibrio cholerae which causes cholera, it was unclear whether a homolog of VtrC also existed in this bacterium or in any other bacterium.
“We had never seen anything like VtrC,” Dr. Kinch said. “But, we thought, other proteins like this must exist.”
With no known genes with sequence identities similar to VtrC, the researchers turned to software released just two years ago called AlphaFold. This artificial intelligence program can accurately predict the structure of certain proteins based on the genetic sequence that encodes them – information that was previously only gleaned through painstaking lab work.
AlphaFold showed that a protein called ToxS in V.cholerae has a very similar structure to VtrC, even though the two proteins do not share any recognizable part of their genetic sequences. When the researchers searched for proteins with similar structural features in other organisms, they found homologs of VtrC in several other species of enteric bacteria responsible for human disease, including Yersinia pestis (which causes bubonic plague) and Burkholderia pseudomallei (which causes a tropical infection called melioidosis). Each of these VtrC homologs appears to work in concert with proteins structurally similar to VtrA, suggesting that their roles may be the same as those of VtrA. V. parahaemolyticus.
Dr. Orth said these structural similarities could eventually lead to pharmaceuticals that treat conditions caused by different infectious organisms that rely on similar pathogenic strategies.
Dr. Orth is a Howard Hughes Medical Institute Scholar, Earl A. Forsyth Professor of Biomedical Sciences, and WW Caruth, Jr. Fellow in Biomedical Research. Member of the National Academy of Sciences since 2020, here is his inaugural article in PNAS.
Reference: Kinch L, Cong Q, Jaishankar et al. Co-component signal transduction systems: Rapidly evolving virulence regulatory cassettes discovered in enteric bacteria. Proceedings of the National Academy of Sciences. 2022;119(24):e2203176119. doi: 10.1073/pnas.2203176119.
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