Files and links (1)
Jarboe_Brianna_20259.60 MB
PDF Embargoed Access, Embargo ends: 31 Aug 2027
Dissertation
Analysis and prediction of E2 enzyme-E3 ligase pairings using AlphaFold-modeled ternary complex structures
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2025
DOI:
https://doi.org/10.17918/00011123
Abstract
Ubiquitination serves as a primary mechanism for targeting proteins for degradation, thereby ensuring proteostasis and controlling the abundance of nearly all cellular proteins. In addition to its global role in protein turnover, ubiquitination, through the activity of specific E3 ligases, plays a critical role in regulating diverse cellular processes. Furthermore, PROTACs and related proximity-inducing agents have revealed the significant therapeutic potential of co-opting ubiquitin ligase activity to induce the selective degradation of disease-relevant proteins. Beyond degradation, ubiquitination can also mediate new protein-protein interactions and modulate protein function, thereby regulating signal transduction, DNA repair, and immune responses. Despite the biological and clinical significance of this pathway, fundamental gaps remain in our understanding, particularly regarding the specificity of E2-E3 interactions and their substrate preferences. In this study, we leverage AlphaFold to generate structures of thousands of ubiquitin-E2-E3 ternary complexes. Using these structures and complementary analyses, we develop a machine learning model to predict functional E2-E3 pairings, advancing our ability to map ubiquitination networks and providing structural insights into functional ubiquitin-E2-E3 complexes. We demonstrate the utility of this model by predicting E2 partners for 88 E3 ligases lacking any previously known E2 interactors. Notably, we identify a predicted pairing between UBE2C and RNF214, two proteins recently implicated in hepatocellular carcinoma through independent mechanisms, suggesting a possible functional link mediated by RNF214-dependent ubiquitination in conjunction with UBE2C. We additionally present a web-resource, Ub-PredicTernary, making the results of this work readily available to the scientific community.
Metrics
21 Record Views
Details
- Title
- Analysis and prediction of E2 enzyme-E3 ligase pairings using AlphaFold-modeled ternary complex structures
- Creators
- Brianna Jarboe
- Contributors
- Roland L. Dunbrack Jr. (Advisor) - Fox Chase Cancer Center
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 108 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022072595204721