Award Date

12-15-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Committee Member

Gary Kleiger

Second Committee Member

Ernesto Abel-Santos

Third Committee Member

Hong Sun

Fourth Committee Member

Boo Shan Tseng

Number of Pages

210

Abstract

Homeostasis, the process of maintaining stable biochemical and biophysical conditions, is a fundamental facet of cellular viability. Biochemical homeostasis is critical to support the biological functions that sustain living organisms. Protein ubiquitylation is one of the primary cellular pathways that regulate protein homeostasis and turnover. Ubiquitylation is initiated through the conjugation of a small globular protein known as ubiquitin, onto a given substrate. There exists a myriad of cellular fates that ubiquitylated proteins may undergo, but the most widely studied pathway is protein degradation, whereby a ubiquitylated protein substrate is shunted to a large macromolecular protease known as the proteasome, where it is degraded. Since ubiquitylation is involved in nearly all cellular metabolic pathways and is implicated in the pathogenesis of many diseases, the study of the enzymes that govern ubiquitylation has garnered significant attention.

One of the largest classes of enzymes that is closely involved in ubiquitylation are cullin-RING ubiquitin ligases (CRLs). CRLs are multi-subunit, modular enzymes that contain a cullin scaffold, and a substrate receptor module that binds proteins destined for ubiquitylation. The catalysis of ubiquitylation occurs when a CRL encounters a ubiquitin-carrying enzyme (UCE), a class of enzymes that can either initiate ubiquitylation by conjugating the first ubiquitin onto a protein substrate, or by forging poly-ubiquitin chains.

The prevailing knowledge of the relationship between CRLs and UCEs is relatively weak, owing to a lack of investigations into UCEs specifically. Furthermore, the molecular mechanisms of substrate priming and poly-ubiquitin chain extension by these UCEs are not well understood. Therefore, the aims of the studies in this dissertation are to (1) to interrogate the complex partnership between CRLs and UCEs, and (2) elucidate the molecular mechanisms underlying substrate priming and poly-ubiquitin chain extension, in the context of CRLs

Controlled Subject

Biochemistry; Homeostasis; Enzymology

Disciplines

Biochemistry, Biophysics, and Structural Biology | Chemistry | Physical Sciences and Mathematics

File Format

PDF

File Size

4900 KB

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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