Examination of the many regulatory roles of intrinsically disordered proteins
Restricted (Penn State Only)
- Author:
- Usher, Emery
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology (PHD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 21, 2022
- Committee Members:
- David Gilmour, Major Field Member
Scott Showalter, Chair & Dissertation Advisor
Song Tan, Major Field Member
Scott Lindner, Outside Unit Member
Amie Boal, Outside Field Member
Wendy Hanna-Rose, Program Head/Chair - Keywords:
- intrinsically disordered proteins
nuclear magnetic resonance
NMR
thermodynamics
biochemistry
biophysics
transcription
regulation
phosphorylation
proteins - Abstract:
- Intrinsically disordered proteins—proteins that lack stable 3-D structure—are paramount to cellular function in health and disease. Intrinsically disordered proteins (IDPs) are found in all domains of life and are central regulators of myriad processes including transcription, signal transduction, and cell cycle regulation. Although they lack the catalytic cores of their folded counterparts, IDPs are uniquely suited to regulatory functions due to their dynamic and heterogeneous structures. Large, solvent exposed regions make IDPs excellent mediators of protein-protein interactions; often such interactions are tailored by chemical or structural modification of the IDP, which allows for fine-tuned regulation via disordered protein regions by the fluctuating cellular environment. In line with their crucial regulatory roles, understanding how IDPs carry out their diverse functions with spatial and temporal precision is imperative toward devising general and unique mechanisms of IDP-coordinated regulation. In this dissertation work, I investigate the many contributions to regulated gene expression with particular focus on intrinsically disordered proteins. Using structural biology, thermodynamics, and cell biology approaches, I interrogate the biophysical behavior of the C-terminal intrinsically disordered region of the pancreatic transcription factor Pdx1 and how its IDP properties serve to Pdx1 transcriptional activation ability. One way in which IDPs, including Pdx1, regulate their interactions and functions is through the accumulation of post-translational modifications that impart structural and functional consequences. I also present in vitro characterization of IDP post-translational modifications using NMR spectroscopy and assess consequences of such modifications on IDP intermolecular interactions. Broadly, this dissertation addresses the layers of regulation that support specific control of cellular processes via intrinsically disordered protein regions.