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REGULATION OF UBIQUITIN SIGNALING PATHWAYS BY ADAPTOR PROTEINS

thesis
posted on 2023-05-30, 20:14 authored by Sebastian KennySebastian Kenny

  

Ubiquitination is a post-translational modification that activates a variety of signaling pathways. The process of tagging ubiquitin (Ub) onto a substrate protein requires three proteins. First, the E1-activating protein primes Ub for attachment to the E2-conjugating enzymes. The E2-conjugating enzyme then brings Ub to E3 ligases, which also recruit the substrate proteins. The final step of this cascade is the transfer of Ub onto the substrate protein. More commonly, ubiquitinated proteins are then degraded via the proteasome. This cascade to downregulate proteins is employed as a cellular adaptation mechanism in response to various threats, including bacterial and viral pathogens. Although the Ub system exists exclusively in eukaryotes, in recent years many bacterial effector proteins and viral factors have been shown to hijack the system through highly regulated mechanisms. In my Ph.D. work, I characterized the hijacking mechanism of a protein produced by human papillomavirus (HPV) that causes downregulation of p53. Downregulation of p53 leads to the oncogenic effects of HPV infection. A strain of oncogenic HPV, HPV-16, produces the E6 protein, which forms a complex with the human ubiquitin E3 ligase, E6AP. This allows E6AP to recognize p53 for ubiquitination. Furthermore, the ability of E6 to act as an adaptor protein to target unnatural substrate proteins has been employed by medicinal chemists as the basis of proteolysis targeting chimeras (PROTACs). To this extent, my thesis covers three broad ideas that will add to our understanding of 1) Cellular adaptor protein regulation, 2) viral adaptor protein hijacking, and 3) PROTAC ligand development.

Funding

American Heart Association Predoctoral Fellowship #905924

History

Degree Type

  • Doctor of Philosophy

Department

  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Chittaranjan Das

Additional Committee Member 2

Mark Lipton

Additional Committee Member 3

Angeline Lyon

Additional Committee Member 4

Leifu Chang

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