Inside each cell of the human body are proteins that control which genes are expressed at the right place and time. However, intriguingly, many of the most important proteins involved in gene regulation lack stable structure. Exactly how these disorganized molecules give rise to precise gene expression has become a highly debated question in the field of molecular biology.
Disordered regions make up large portions of many proteins involved in gene regulation. In recent years, scientists had come to believe that all gene-regulating proteins made up of flexible or "floppy" regions worked together by interacting at the microscopic scale in a diffuse way similar to oil droplets that fuse together.
Now, researchers at Baylor College of Medicine have discovered that key components of this machinery instead rely on a structured "bridge" protein to interact and carry out gene activation.
Baylor scientists studied this issue using factors called "BAF complexes," which open DNA, a key early step needed to make genes ready for expression.
"The majority of each BAF complex is disordered and acts like a floppy noodle without a structure," said Dr. H. Courtney Hodges, senior corresponding author of the study and associate professor of molecular and cellular biology and with the Center for Environmental Health at Baylor. "Without a fixed shape, it has been difficult to analyze how these disordered regions interact."
In the new paper published in Molecular Cell, Hodges and an international team of colleagues show that disordered parts of BAF use a protein called beta-catenin as an adapter to link up with other proteins.
"Beta-catenin has a stable molecular structure that acts like a docking station so the noodle-like regions of other proteins can stick together and function properly," said Hodges. "Beta-catenin links together BAF and other disordered proteins involved in gene regulation."
Hodges and his collaborators first began by studying adrenocortical carcinoma (ACC), an aggressive adrenal cancer that produces high levels of steroids. The team sought to find the molecular contacts that explain how this cancer causes hormonal imbalances that can lead to depression, immune suppression and other symptoms.
"We aimed to understand the root molecular mechanisms driving these hormone disruptions to find a better way to treat this disease," said Dr. Yuen San Chan, first author of the study and postdoctoral researcher with Hodges.
The researchers focused on factors that control expression of enzymes involved in steroid hormone production in ACC tumors. Their results revealed that the disordered regions on BAF interact with the structured region of beta-catenin directly, enabling BAF to find and open genes encoding steroid enzymes.
Excitingly, the researchers found that this mechanism isn't unique to steroid hormone production. Other major regulators of gene expression - including proteins involved in stress responses, stem cell maintenance and cancer progression - also rely on beta-catenin to link up with BAF.
"Our findings challenge the way we think about disorder in biology. Interactions between disordered molecules with structured protein give rise to a kind of hidden organization," said Dr. Katerina Cermakova, co-corresponding author and assistant professor of biochemistry and molecular pharmacology at Baylor. "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.
Collaborating institutions include MD Anderson Cancer Center, the Institute of Organic Chemistry and Biochemistry in Czech Republic, the University of Michigan and the University of Colorado School of Medicine.
Others who contributed to the research include Qinyu Gao, Sarah A. Robinson, Wenzhi Wang, Ruzena Filandrova, Lisa-Maria Weinhold, Mario Loeza Cabrera, Miao Zhang, Chandra Shekar R. Ambati, Antonio M. Lerario, Nagireddy Putluri, Katja Kiseljak-Vassiliades, Margaret E. Wierman, Mouhammed Amir Habra, Gary D. Hammer and Vaclav Veverka. For funding information please see the publication.
