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dc.contributor.advisorDobens, Leonard L.
dc.contributor.advisorHonigberg, Saul M.
dc.contributor.authorNauman, Christopher Eric
dc.date.issued2020
dc.date.submitted2020 Summer
dc.descriptionTitle from PDF of title page viewed August 31, 2020
dc.descriptionDissertation advisors: Leonard L. Dobens and Saul Honigberg
dc.descriptionVita
dc.descriptionIncludes bibliographical references (pages 155-174)
dc.descriptionThesis (Ph.D.)--School of Biological Sciences. University of Missouri--Kansas City, 2020
dc.description.abstractMembers of the Tribbles (Trb) family of pseudokinases have roles in development, cell cycle control, insulin signaling, and the immune response and have been linked to many human diseases. The structure of Drosophila Tribbles includes a conserved kinase-like core that binds targets and an N-terminal region that contains a PEST domain, and a Carboxy-terminal tail that binds the E3 ligase, constitutive photomorphogenic I (COP1, Murphy et al., 2015; Jamieson et al., 2018). The bound COP1 ubiquitin-ligase ubiquitinates the target protein, leading to degradation of the target by the proteolytic machinery (Murphy. et al., 2015; Jamieson et al., 2018). The C-terminal tail of Tribbles is responsible for recruiting ubiquitination complexes that target proteins such as String (Stg) and Slow border cells (Slbo) for proteolytic degradation. While Drosophila Tribbles (Trbl) retains this conserved function, it lacks a C-terminal COP1 binding site found in most Trb family members that have been shown necessary for target protein destruction. To uncover the cryptic binding site, we misexpressed Tribbles and mutant variants in Drosophila tissue, including the wing and egg chamber to determine function. Multiple sequence alignments of closely and distantly related Tribbles proteins in arthropods determined that the divergence from a COP1 binding site in fly Tribble is a recent evolutionary event. Motif scans led to the discovery of a PEST domain in the C-terminal tail and site-directed mutagenesis of the PEST domain revealed its importance for Trbl function. Genetic interaction with the Cullin 3 proteome adaptor protein has shed light on a possible mechanism of Trbl tail function.
dc.description.tableofcontentsIntro -- A Structure function analysis of drosophila tribbles identifies an important region necessary for recruiting ubiquiti ligases -- Screening of a drosophila orf library for interactors of the Pseudokinase tribbles identifies neutralized and Mindbomb, ubiquitin ligases that mediate notch signaling -- A structure*function analysis of drosophila tribbles reveals conserved features required for stability and subcellular distribution -- Future directions
dc.format.extentxiv, 176 pages
dc.identifier.urihttps://hdl.handle.net/10355/75784
dc.subject.lcshDrosophila
dc.subject.lcshProtein kinases
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Biology
dc.titleStructure-Function Analysis of the Tribbles Pseudokinase
thesis.degree.disciplineMolecular Biology and Biochemistry (UMKC)
thesis.degree.disciplineCell Biology and Biophysics (UMKC)
thesis.degree.grantorUniversity of Missouri--Kansas City
thesis.degree.levelDoctoral
thesis.degree.namePh.D. (Doctor of Philosophy)


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