Researchers at Baylor College of Medicine, the Czech Academy of Sciences and others have discovered a brand new piece of information on the way that gene expression functions. Published in the journal Science, the findings reveal a novel mechanism that coordinates the assembly of components inside cells that regulate gene expression. The mechanism not only is essential for normal cell function, but has been implicated in neurodegeneration, cancer and HIV infection, and may provide new methods to treat these conditions.
“Most previous studies have concentrated on particular cell components that turn genes completely on or off,” said co-corresponding author Dr. H. Courtney Hodges who is an assistant professor of molecular and cell biology and the Center for Precision Environmental Health at Baylor. “Our research provides a fresh perspective that proteins that regulate gene expression also be used in conjunction to fine-tune expression levels in various environments. We have discovered a mechanism that combines these proteins and plays many different roles in both health and in disease.
The team has previously collaborated with colleagues from KU Leuven in Belgium to study protein interactions in leukemia and HIV infection, and more specifically those that are mediated by protein regions called TFIISN-terminal domains. In the current study, the researchers extended the study of TNDs and found they were present in a variety of other proteins.
“We discovered these domains everywhere we searched,” Dr. Katerina Cermakova, whose research focuses on the mechanism that regulates transcription expansion, which is among the initial steps in gene expression in all human cells. Transcription elongation can be described as a complex cellular process that involves many different proteins that work together,” said first author Dr. Katerina Cermakova, a postdoctoral researcher in the Hodges lab. “We discovered that TNDs were the most enriched structural element of all transcription elongation factor transcription factors. When you search for them, you’ll find that all the important protein complexes involved in the process of transcription elongation possess an TND or are bound to an element that has one.”
The researchers have previously suggested that TNDs act as docking platforms to other protein regions, especially for small amounts of unstructured proteins known as TND-interacting motif.
Proteins can be classified into segments with an organization in 3-D, however, there are many segments that don’t have this structure. These disordered or unstructured regions are usually functional.
“One of the most fascinating things about these unstructured spaces is their unique behavior in molecules,” said Dr. Vaclav Veverka (co-corresponding author), structural biologist and group leader at IOCB Prague’s Institute of Organic Chemistry and Biochemistry. Imagine a TIM being loose at one end and moving in a storm. But when it finds its TND partner, the string is able to curl up and clings very tightly to the TND to keep it close.” The research team has demonstrated that this attachment plays a significant part in the beginning stages of gene expression.
Cermakova stated that she first discovered that TNDs and TIMs were bound together in a test tube experiment, but it was exciting to see them bind to each other in living cells. This validated our observations in living systems. “We also found that TND-TIM interactions are very specific.”
“I was shocked to discover IWS1, previously believed to be a secondary actor in the transcription elongation process and is the central organisator of these variables,” Hodges, Baylor’s Dan L Duncan Comprehensive Cancer Center member Hodges, Baylor’s Dan L Duncan Comprehensive Cancer Center member, said.
Veverka stated that IWS1 uses TND-TIM interactions in order to coordinate the activities of multiple transcription regulators at once. This makes it appear as the conductor in a symphony that ensures that all elements are working in harmony.
The team also looked into the effects of disrupting a single unstructured protein region on the balance of the transcription elongation process.
“Hundreds of genes with crucial functions were altered after we disrupted just one unstructured region,” Hodges said. “The first step of gene expression started, but was paused and was unable to complete and impeded the expression of genes.”
The study reveals the under-appreciated role of disordered protein interactions as the key orchestrators of gene expression and other intricate biological functions. The findings also can help in the better understanding of diseases like cancer as well as viral infections, neurodevelopmental disorders and other conditions in which these elements are affected. These new targets could be crucial to improve treatment for these conditions.
Cermakova, K., et al. (2021) A ubiquitous disordered protein interplay module orchestrates transcription elongation. Science. doi.org/10.1126/science.abe2913.
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