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Date of Award

5-2012

Document Type

Campus Access

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Neuroscience and Behavior

First Advisor

John R. Nambu

Second Advisor

Elizabeth A. Connor

Third Advisor

Lawrence M. Schwartz

Subject Categories

Cell Biology | Genetics | Molecular Biology

Abstract

The Drosophila morgue gene was identified as a regulator of programmed cell death and protein ubiquitination. It has been shown to enhance programmed cell death via promoting the turnover of DIAP1, a conserved anti-apoptotic protein. Morgue protein contains a zinc finger motif, an F box domain and a ubiquitin E2 conjugase variant domain with a Cysteine to Glycine substitution at the catalytic site. This unique domain/motif architecture suggests that Morgue may have very distinctive activities. However, how and what each domain/motif contributes to Morgue function remains unexplored. My dissertation project focused on a study of Morgue protein evolution and function using a combination of bioinformatics, genetics and biochemical methods. The results suggest that Morgue exhibits widespread but restricted phylogenetic distribution among invertebrate metazoans; the study of Morgue's origin provides an example of how multi-domain proteins may evolve. Results of functional studies revealed that over-expression of Morgue can induce a homozygous lethal phenotype that is independent of either F-box or the Glycine in the UEV domain. In addition, co-immunoprecipitation experiments have shown that Morgue associates with SkpA and Lys48 linked polyubiquitin chains, indicating that Morgue might be a multi-functional protein in PCD and ubiquitination.

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