How Disordered Proteins Regulate Gene Expression

Researchers at Baylor College of Medicine have uncovered how proteins with unstable structures can regulate gene expression with precision, a finding that challenges previous views in molecular biology. Many proteins involved in gene regulation consist largely of disordered regions, and while these “floppy” areas lack fixed structure, they still manage to control vital cellular functions. The new study, published in Molecular Cell, reveals how these disordered proteins interact using a structured intermediary.

The research focused on BAF complexes, which help open up DNA to allow genes to be expressed. Although most of the BAF complex lacks a defined form—“like a floppy noodle without a structure,” as described by senior author Dr. H. Courtney Hodges—his team discovered that BAF’s disordered regions can function through a rigid bridging protein called beta-catenin. This protein acts as a structural “docking station,” enabling BAF and other disordered proteins to assemble and perform their roles.

The study began with a focus on adrenocortical carcinoma (ACC), a rare adrenal cancer linked to steroid hormone imbalance. First author of the study Yuen San Chan explained that the goal was to uncover mechanisms prompting hormone disruptions in hopes of improving treatment. The team found that BAF’s disordered regions interact directly with beta-catenin to activate genes responsible for steroid hormone production.

Importantly, the researchers discovered that this interaction model extends beyond ACC. Other critical regulators of gene expression—including those linked to stress, stem cells, and cancer—also rely on beta-catenin to organize and guide disordered proteins.

“Our findings challenge the way we think about disorder in biology,” said co-author Dr. Katerina Cermakova. “We’ve shown how disordered gene-regulating proteins find and bind specific targets.”

The team’s findings reveal that despite their disordered nature, the protein interactions that drive gene expression are surprisingly modular and even have an underlying organization. While more work is needed, the team’s work shows that the involved factors may be potential targets for drug development and therapies.