Designing proteasome adaptors to deplete specific proteins from cells

dc.contributor.advisorMatouschek, Andreas T.
dc.contributor.committeeMemberXhemalce, Blerta
dc.contributor.committeeMemberHuibregtse, Jon
dc.contributor.committeeMemberGeorgiou, George
dc.contributor.committeeMemberDalby, Kevin
dc.creatorBowen, Kimberly Elizabeth
dc.date.accessioned2019-07-08T21:02:38Z
dc.date.available2019-07-08T21:02:38Z
dc.date.created2019-05
dc.date.issued2019-06-21
dc.date.submittedMay 2019
dc.date.updated2019-07-08T21:02:38Z
dc.description.abstractCellular protein levels are governed by their rates of synthesis and degradation, and both processes are intricately regulated. One way to study the role of a protein in the cell is to artificially deplete it and observe the effects. The most common methodology for depleting proteins inhibits expression of the target through RNA interference. However, this technique acts at the protein synthesis level and cannot be used to study long-lived proteins or post-translational modifications. Thus, a complementary approach that acts on the proteins themselves would be useful. One method is to target a protein to the cell’s degradation machinery, the Ubiquitin Proteasome System (UPS). Proteins are targeted to the proteasome by the covalent attachment of ubiquitin molecules, which are recognized by the proteasome. The substrate is then translocated into the proteasome’s proteolytic core and degraded into short peptides, while the ubiquitin molecules are cleaved off and recycled. Recently, methods have been developed to deplete proteins by inducing their ubiquitination, which accelerates their degradation by the proteasome. Ubiquitin is a signaling molecule for numerous cellular pathways other than proteolysis, however, and inducing ubiquitination does not always lead to degradation. Therefore, I have developed a system to degrade specific proteins in cells using chimeric adaptors that shuttle proteins directly to the proteasome without the need for ubiquitination. I have shown that this system can be successfully applied to several proteins in vitro and that the adaptors can induce degradation of model and endogenous proteins in cells.
dc.description.departmentCellular and Molecular Biology
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152/75067
dc.identifier.urihttp://dx.doi.org/10.26153/tsw/2174
dc.language.isoen
dc.subjectProteasome
dc.subjectDegradation
dc.subjectShp2
dc.subjectAbl
dc.titleDesigning proteasome adaptors to deplete specific proteins from cells
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentCellular and Molecular Biology
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorThe University of Texas at Austin
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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