Disordered Protein Interactions Have Key Role in Gene Expression

A study published last week in Science highlights the role of disordered protein interactions as key orchestrators in gene expression and other complex biological functions.

“Most previous studies have focused on particular cellular components that turn genes completely on or off,” said co-corresponding author H. Courtney Hodges from Baylor College of Medicine. “Our work reveals a new perspective—that the proteins that regulate the rate of gene expression also can work collectively to finely tune expression levels in many different settings. We identified a mechanism that brings these proteins together and plays widespread roles in health and disease.”

In previous work, the team had studied protein interactions in leukemia and HIV infection, specifically those mediated by protein regions called TFIIS N-terminal domains (TNDs). In the current study, the researchers extended the study of TNDs and found them in many other proteins.

“Everywhere we looked, we found these domains, in particular in the machinery that regulates transcription elongation, one of the first steps of gene expression in all human cells. Transcription elongation is a complex cellular process that involves many different proteins working together,” said first author Katerina Cermaova. “We discovered that TNDs are the most enriched structural element in all transcription elongation factors. Once you look for them, you find that all the important protein complexes involved in transcription elongation have a TND or bind a protein that has one.”

Proteins have segments with a well-organized 3-D structure, but many also have segments that lack such organization. These disordered or unstructured regions are often functional. “One remarkable thing about these unstructured regions is their unusual behavior as molecules,” said co-corresponding author Vaclav Vevera. “Imagine a TIM as a string that is loose at one end and moves as if being blown around in a hurricane. But when it finds its TND partner, the string curls up and holds on very tightly to the TND to keep it close.” The researchers show this attachment plays an important role in the early stages of gene expression.

“We first determined that TNDs and TIMs bound together in ‘test tube’ type of experiments, but it was really exciting to see that they bind to each other in living cells, validating the relevance of our observations in living systems,” Cermakova said. “We also determined that the TND-TIM interactions are highly specific.”