The objective of this project is to understand how transcription factors and other signaling proteins utilize intrinsic disorder (ID) to facilitate their function. Over the past 3 decades it has become increasingly clear that rather than existing as static structures, proteins are actually ensembles of sometimes very different conformational states, and that fluctuations and disorder are critical to function. It is of great import to know how this is done. Are there unifying principles that connect proteins with different functions? Here we take advantage of two discoveries by our group, which demonstrates that the transcription factor glucocorticoid receptor (GR) uses disorder-to-order transitions to facilitate function ? in effect, the energy landscape has ID within its functionally important repertoire. We find that ID regions communicate both with other ID regions, as well as structured domains. Furthermore, we show that GR employs thermodynamic frustration, wherein the molecule simultaneously codes for activation and repression, and that GR controls the degree of the repression by producing different isoforms from alternative translation start sites. How does GR do this? What are the structural and dynamic determinants of communication between domains? We will perform binding, stability and in vivo activity measurements and we will use high-resolution NMR structural and dynamic techniques to characterize the molecular basis of the observed behavior.

Public Health Relevance

Intrinsic disorder is found in hyper-abundance in transcription factors, and it is known to be important in mediating allostery. Understanding how this is done is not just academic. As steroid hormone receptors, which are studied here, have been implicated in several cancers, and have been the target of numerous therapeutic interventions, insights into how allostery is linked to function can dramatically improve rational design outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM126130-01
Application #
9425728
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205