A recent collaborative study from scientists at Princeton University, the Dana-Farber Cancer Institute, and Washington University in St. Louis has demonstrated that the intrinsically disordered regions (IDRs) of proteins are crucial for gene expression and chromatin regulation in cells. The research, published in the journal Cell, challenges longstanding beliefs about protein structure and function. The study was underwritten by various organizations, including the Howard Hughes Medical Institute and the National Science Foundation.
Traditional understanding posits that proteins achieve functionality by folding into stable three-dimensional shapes that interact precisely with other biomolecules. However, this portrayal of proteins as the “biological workhorses” is incomplete. Approximately half of all proteins contain unstructured, thread-like sections known as IDRs.
The prevalent notion in biology has been that IDRs, due to their fluid and shape-shifting geometries, do not engage as precisely with other biomolecules as their more structured counterparts do. Consequently, they were thought to be of lesser importance to overall protein function.
This multi-institutional research refutes such assumptions by revealing the critical role IDRs play in chromatin regulation and gene expression, processes vital to all living cells. The focus was on the IDRs within the human cBAF complex, a collection of proteins in the cell nucleus responsible for unpacking tightly coiled DNA, termed chromatin, thereby facilitating gene expression.
The study showed that mutations in the IDRs of specific cBAF subunits—particularly ARID1A and ARID1B—are prevalent in conditions such as cancer and neurodevelopmental disorders. These mutations significantly disrupt chromatin organization and gene expression, indicating that IDRs are far from inconsequential.
Furthermore, the study disclosed that IDRs form small droplets, or condensates, that segregate from the surrounding cellular fluid, similar to oil droplets in water. These condensates are venues for specific interactions that enable proteins and other biomolecules to cluster and execute cellular activities.
Until this research, it was unclear whether these specialized condensates played any role in chromatin regulation or if their specific amino acid sequences had particular functions. The investigation also examined the impact of different mutations in ARID1A/B IDRs on the ability of the cBAF protein complex to create condensates and attract necessary proteins for gene expression.
The findings offer valuable insights into how mutations in IDRs contribute to disruptions in cellular processes and could pave the way for new therapeutic interventions. Amy Strom, co-lead author of the study, emphasized that the findings have broad applications and could significantly impact our understanding of cellular functions.
The study represents a comprehensive effort from multiple institutions and experts. Its implications extend not just to understanding the mechanisms of cBAF chromatin remodeling complexes, a prime focus in oncology, but also to gaining a deeper comprehension of the previously underestimated importance of IDR protein sequences in physiology and disease.
Frequently Asked Questions (FAQs) about Intrinsically Disordered Regions in Proteins
What is the primary focus of the new research?
The primary focus of the new research is to examine the role of intrinsically disordered regions (IDRs) in proteins, particularly in relation to gene expression and chromatin regulation. The study challenges the conventional understanding that these unstructured regions are of lesser importance to overall protein function.
Who conducted the research?
The research was conducted through a collaboration between scientists at Princeton University, the Dana-Farber Cancer Institute, and Washington University in St. Louis.
What have traditional views posited about protein structure and function?
Traditional views have posited that proteins gain their functionality by folding into stable three-dimensional shapes that interact precisely with other biomolecules. IDRs, being unstructured, were assumed to be less important to the protein’s overall functionality.
What new insights does the research offer?
The research suggests that IDRs play a critical role in gene expression and chromatin regulation. Specifically, mutations in IDRs can significantly disrupt these processes, implying that IDRs are far from being trivial or inconsequential.
What are IDRs and why are they important according to the study?
Intrinsically Disordered Regions (IDRs) are unstructured, thread-like sections of proteins. According to the study, they are crucial for processes like gene expression and chromatin regulation. IDRs form small droplets or condensates that act as venues for specific interactions among proteins and other biomolecules, enabling them to cluster and execute cellular activities.
How could this research impact therapeutic strategies?
The study’s findings offer valuable insights into how mutations in IDRs contribute to disruptions in cellular processes. This could pave the way for the development of new therapeutic interventions, particularly in conditions such as cancer and neurodevelopmental disorders where IDR mutations are frequent.
Who funded the research?
The research was funded in part by the Howard Hughes Medical Institute, the Air Force Office of Scientific Research, the St. Jude Children’s Research Hospital, the Mark Foundation for Cancer Research, and the National Science Foundation.
Where was the research published?
The research was published in the journal Cell. The article is titled “A disordered region controls cBAF activity via condensation and partner recruitment” and was released on October 3, 2023.
What are the implications of the study for the field of oncology?
The study has significant implications for the field of oncology, particularly concerning cBAF chromatin remodeling complexes, which are among the top targets in cancer research. Understanding the role of IDRs could provide new avenues for therapeutic targeting.
Are there any surprising elements that came out of this research?
One surprising element is the degree to which even subtle disease-associated perturbations in IDR sequences altered the function of major chromatin remodelers along the genome. This led researchers to explore the specific changes down to the amino acid level.
More about Intrinsically Disordered Regions in Proteins
- Original Research in the Journal Cell
- Princeton University Research
- Dana-Farber Cancer Institute
- Washington University in St. Louis
- Howard Hughes Medical Institute
- National Science Foundation
- Chromatin Regulation: An Overview
- Introduction to Proteins
- Gene Expression and Its Importance
- Therapeutic Targeting in Oncology