Kim Orth, Ph.D.
DALLAS — June 30, 2022 — Using artificial intelligence, UT Southwestern researchers have discovered a new family of sensing genes in gut bacteria that are linked by structure and likely function, but not 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 bacterial intestinal infections.
“We identified similarities in these proteins in the reverse order of how it’s usually done. Instead of using sequence, Lisa looked for similarities in their structure,” said Kim Orth, Ph.D., professor of Molecular Biology and Biochemistry, who, along with Lisa Kinch, Ph.D., a bioinformatics specialist in the Department of Molecular Sciences Biology.
The lab of Dr. Orth has long focused on studying how marine and estuary bacteria cause infections. In 2016, Dr. Orth and her colleagues biophysics to characterize the structure of two proteins called VtrA and VtrC complex that work together in a bacterial species known as Vibrio parahaemolyticus† She and her team then discovered the VtrA/VtrC complex in V. parahaemolyticus – which is often the cause of food poisoning from contaminated crustaceans – detects bile from the bacterial cell surface and sends a signal to launch a chemical cascade that prompts this microbe to enter 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 causes cholera, it was unclear whether a homologue for VtrC also existed in these or other bacteria.
“We had never seen anything like VtrC,” said Dr. chin. “But, we thought, other proteins like this must exist.”
Without any 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 some proteins based on the genetic sequence that encodes them — information previously obtained only through painstaking work in the lab.
Membrane signaling system of gut-infecting bacteria
AlphaFold showed that a protein called ToxS in V. cholerae very similar in structure to VtrC, although the two proteins did not share recognizable parts of their genetic sequences. When the researchers looked for proteins with similar structural features in other organisms, they found homologues for VtrC in several other enteric bacterial species responsible for human disease, including Yersinia pestis (which causes the bubonic plague) and Burkholderia pseudomallei (which causes a tropical infection called melioidosis). Each of these VtrC homologs appears to interact with proteins similar in structure to VtrA, suggesting that their role could be similar to those in V. parahaemolyticus†
dr. Orth said these structural similarities could eventually lead to drugs that treat conditions caused by different infectious organisms that rely on similar pathogenic strategies.
dr. Orth is a Howard Hughes Medical Institute investigator who holds the Earl A. Forsyth Chair in Biomedical Sciences and a W.W. Caruth, Jr. Scholar in Biomedical Research. Member of the National Academy of Sciences since 2020, this is her inaugural article in PNAS†
Other UTSW researchers who contributed to this study include Qian Cong, Ph.D., a Southwestern Medical Foundation Scholar in Biomedical Research, and Jananee Jaishankar, Ph.D.
This study was funded by grants from The Welch Foundation (I-1561), Once Upon a Time Foundation, and the National Institutes of Health (R01 GM115188).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates cutting-edge biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 members is responsible for pioneering medical advances and is committed to quickly translating science-based research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency care cases, and oversee nearly 4 million outpatient visits each year.