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Chowdhury publishes study on proteins in cells that could help in treatment of disease

Saiful Chowdhury
Saiful Chowdhury

A chemistry researcher at The University of Texas at Arlington has led a study focusing on proteins in cells which could have important implications in the treatment of both high cholesterol and disease-causing microorganisms in the body.

Saiful Chowdhury, associate professor of chemistry and biochemistry, authored a study which was published in the September 2019 edition of the prestigious proteomics journal Molecular and Cellular Proteomics. The paper is titled “Cross-linking Proteomics Indicates Effects of Simvastatin on the TLR2 interactome and Reveals ACTR1A as a Novel Regulator of the TLR2 Signal Cascade,” and the lead author is Abu Hena Mostafa Kamal, a postdoctoral fellow in Chowdhury’s lab.

Chowdhury and his colleagues utilized proteomics — the large-scale study of proteins in cells — to achieve their findings. The study involves a group of proteins called Toll-like receptors (TLRs), which are found in white blood cells called macrophages. TLRs recognize pathogens in the body and initiate responses to attack and kill the pathogens. The project also involves statins, which are drugs used by millions of people that can lower cholesterol by blocking an enzyme in the liver that the body needs in order to make cholesterol.

“For the first time, our group has devised a novel proteomics method to study the protein networks involved in the combined treatment of statins and pathogenic substances from bacteria,” Chowdhury said. “The method we describe in this research will contribute significantly to our ability to understand statin impacts on inflammations and advance protein signaling research.”

The researchers utilized a technique called co-immunoprecipitation, which identifies protein-to-protein interactions by using target protein-specific antibodies to indirectly capture proteins that are bound to a specific target protein.

“This method utilizes an engineered tag in a protein which can be used to pull out that protein from complex mixture using another tag,” Chowdhury said. “This tag is used as a hook to fish out that protein along with its attached interactors. Unfortunately, this method identifies numerous false positive interactions of proteins.”

To address this shortcoming, Chowdhury’s group developed an approach in which they utilized chemical cross-linking to attach the proteins so that after opening the cells, the information of the protein interaction remained intact. They used two different types of cross-linkers which have the capability to reach smaller and reasonably wider distances among proteins. One of these cross-linkers with wider distances was developed by Chowdhury’s group.

“The cross-linker developed by our group in-house has a unique design,” Chowdhury said. “Proteins conjugated with this cross-linker produce two kinds of signature fragment markers when dissociated with a technique called mass spectrometry. So, in large-scale samples these could be used like a mass scanner to locate which protein is bound with which proteins.” 

Combining the co-immunoprecipitation technique with cross-linking, the Chowdhury group studied inflammatory signaling of Toll-like receptors 2 (TLR2) engineered in human embryonic kidney cells. They treated the cells with the statin drug Simvastatin, the pathogenic substance lipopeptide, and sequential treatment of the two.

“We identified for the first time two new proteins in the immune signaling pathways of TLR2 due to this experiment,” Chowdhury said. “One of these proteins, called ACTRA1, we found highly expressed due to only statin treatment. A detailed biochemical experiment found the influence of this protein in the production of inflammatory markers in the statin-treated cells.”

The study was funded by the National Institutes of Health’s National Institute of General Medical Sciences. It is the latest of Chowdhury’s studies in proteomics to be published, following recent papers he co-authored in Journal of Proteome Research, ACS Omega, PLOS One, and Scientific Reports.

He also recently collaborated with UTA Department of Biology faculty members on papers utilizing proteogenomics, the combined study of genomics and proteomics. One paper, with Todd Castoe, associate professor, appeared in the July 2019 edition of Proceedings of the Royal Society B and focuses on snakes’ intestinal tissue proteomics. Another, with Laura Mydlarz, associate professor, appeared in the June 2019 edition of Integrated and Comparative Biology and focuses on proteomic investigation of coral disease.

Fred MacDonnell, professor and chair of the UTA Department of Chemistry & Biochemistry, said Chowdhury’s work further enhances UTA’s reputation of conducting top-tier research in health and the human condition, which is one of the main points of emphasis in the University’s Strategic Plan 2020.

“Dr. Chowdhury’s research in proteomics and bio-analytical mass spectrometry has the potential to yield groundbreaking results in protein biomarkers and structural biology research,” MacDonnell said. “He and his colleagues’ efforts are indicative of the great work being done in the Department of Chemistry & Biochemistry and the College of Science in general.”

Chowdhury came to UTA in 2012 from the National Institute of Environmental Health Sciences, NIH, where he conducted research on host-defense proteomics. One of his recent papers in Scientific Reports was listed among the top 100 most accessed articles in the category of cell and molecular biology for 2018.

He was named by the Journal of the American Society of Mass Spectrometry in 2017 as one of the top emerging investigators in the field worldwide. He earned his Ph.D. in Analytical Chemistry from Washington State University in 2006 and did postdoctoral research in a world-renowned proteomics group in the Pacific Northwest National Laboratory in Washington.