Regulation of elongation factor 2 kinase (eEF-2K) by acidity
dc.contributor.advisor | Dalby, Kevin N. | |
dc.contributor.committeeMember | Fast, Walter L | |
dc.contributor.committeeMember | Brodbelt, Jennifer S | |
dc.contributor.committeeMember | Lee, Seongmin | |
dc.contributor.committeeMember | Mills, Edward | |
dc.creator | Chitjian, Catrina Ann | |
dc.creator.orcid | 0000-0002-8962-3030 | |
dc.date.accessioned | 2019-02-06T16:20:44Z | |
dc.date.available | 2019-02-06T16:20:44Z | |
dc.date.created | 2018-08 | |
dc.date.issued | 2018-08 | |
dc.date.submitted | August 2018 | |
dc.date.updated | 2019-02-06T16:20:44Z | |
dc.description.abstract | Eukaryotic elongation factor 2 kinase (eEF-2K) is a calmodulin (CaM)/calcium regulated kinase whose activity disrupts translation elongation resulting in the global decrease of protein synthesis¹. Translation is one of the most energy intensive processes in a cell; eEF-2K is critical in maintaining cellular homeostasis. The dysregulation of eEF-2K is associated with an assortment of diseases including several types of cancer², depression [superscript 3,4], and Alzheimer’s disease⁵, which has prompted closer examination across multiple studies of the enzyme in recent decades. Notably, the kinetic mechanism of eEF-2K has been detailed as a two-step process: 1) The binding of Ca²⁺-CaM enables the autophosphorylation of Thr-348 and 2) The resulting conformational change enables eEF-2K to bind and phosphorylate its substrate. We have uncovered many surprising layers of eEF-2K regulation in past years, from kinetic mechanism to upstream affecters to models of CaM binding. This study focuses on the role of pH in regulating eEF-2K. pH homeostasis is also vital for cellular function. Even a slight disruption between the intra- and extracellular pH ratio can affect an array of processes such as ATP synthesis, enzyme function, as well as the proliferation, migration, and invasion of tumor cells⁶. Acidosis is a common effect of high intensity exercise, diabetic ketoacidosis, ischemia, and solid tumors [superscript 7–9]. It has been demonstrated that eEF-2K activity is increased and protein translation decreased in cells under acidic conditions, suggesting the enzyme’s potential cytoprotective effects [superscript 10–12]. This work reports the following: 1) A novel mechanism where H⁺ instead of Ca²⁺ activates eEF-2K; 2) A novel mechanism where H⁺ can replace Ca²⁺ in promoting eEF-2K substrate phosphorylation; 3) H⁺ promotes the binding of CaM to eEF-2K in a Ca²⁺-independent manner; 4) There are five histidine residues on eEF-2K that may contribute to the stabilized activity of eEF-2K under acidic conditions. | |
dc.description.department | Cellular and Molecular Biology | |
dc.format.mimetype | application/pdf | |
dc.identifier | doi:10.15781/T2HT2GZ7G | |
dc.identifier.uri | http://hdl.handle.net/2152/72809 | |
dc.language.iso | en | |
dc.subject | eEF-2K | |
dc.subject | Acidity | |
dc.subject | Elongation factor 2 kinase | |
dc.title | Regulation of elongation factor 2 kinase (eEF-2K) by acidity | |
dc.type | Thesis | |
dc.type.material | text | |
thesis.degree.department | Cellular and Molecular Biology | |
thesis.degree.discipline | Cell and Molecular Biology | |
thesis.degree.grantor | The University of Texas at Austin | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Doctor of Philosophy |