Molecular mechanisms involved in the regulation of phosphatidylinositol 4-kinase III α (PI4KIIIα/PI4KA)
| dc.contributor.author | Suresh, Sushant | |
| dc.contributor.supervisor | Burke, John E. | |
| dc.date.accessioned | 2025-10-30T22:54:11Z | |
| dc.date.available | 2025-10-30T22:54:11Z | |
| dc.date.issued | 2025 | |
| dc.degree.department | Department of Biochemistry and Microbiology | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | One of the first steps in the phosphoinositide signalling pathway is the generation of phosphatidylinositol 4-phosphate (PI4P) from phosphatidylinositol (PI). Once considered just an intermediate for phospholipase C (PLC) signalling, PI4P has now emerged as a critical player in membrane trafficking and lipid transport. The predominant pool of PI4P at the plasma membrane is generated by the type III phosphatidylinositol 4-kinase alpha (PI4III/PI4KA). In the cell, PI4KA exists as a large, 750 kDa dimer of heterotrimers along with two accessory proteins, TTC7 and FAM126. Critical to the regulation of PI4KA is its interaction with protein and lipid binding partners. Dysregulation of this pathway leads to severe neurological, gastrointestinal and immunological disorders. Additionally, PI4KA can be hijacked by the hepatitis C virus to promote viral replication and disease. Due to the severe toxicity attributed to existing therapeutics, a deeper understanding of the molecular mechanisms underlying PI4KA regulation is required. In this dissertation, I employed a combination of advanced scientific techniques, including protein biochemistry, bio-layer interferometry (BLI), hydrogen deuterium exchange mass spectrometry (HDX-MS), and cryo-electron microscopy (cryo-EM), to elucidate the molecular basis for the regulation of PI4KA by binding partners, calcineurin and EFR3. This multifaceted approach advances our understanding of how this enzyme is recruited to the membrane, activated at the membrane and regulated at the membrane to better develop targeted therapeutics in disease. This dissertation will consist of an introduction chapter introducing PI4KA signalling, the various players involved in its regulation and its role in disease. It will be followed by two data chapters that expand our knowledge on the regulatory mechanisms by which the enzyme is regulated by proteins, calcineurin and EFR3. The third data chapter aims to put forth the idea of a biochemical tool that may be used to selectively target PI4KA activity in disease. Finally, the last chapter will summarize the research and present future directions in the field. Collectively, the work presented here provides unique insight into how PI4KA is recruited to the membrane, the role of phosphorylation in its regulation and how these regulatory mechanisms can be specifically targeted in disease. | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.bibliographicCitation | Suresh S, Burke JE. Structural basis for the conserved roles of PI4KA and its regulatory partners and their misregulation in disease. Advances in Biological Regulation. 2023 Dec 1;90:100996. | |
| dc.identifier.bibliographicCitation | Shaw AL, Suresh S, Parson MA, Harris NJ, Jenkins ML, Yip CK, Burke JE. Structure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A. Structure. 2024 Nov 7;32(11):1973-83. | |
| dc.identifier.bibliographicCitation | Suresh S, Shaw AL, Pemberton JG, Scott MK, Harris NJ, Parson MA, Jenkins ML, Rohilla P, Alvarez-Prats A, Balla T, Yip CK. Molecular basis for plasma membrane recruitment of PI4KA by EFR3. Science Advances. 2024 Dec 20;10(51):eadp6660. | |
| dc.identifier.bibliographicCitation | Suresh S, Shaw AL, Akintola DK, Lunke M, Doerr S, Rohilla P, Balla T, Yip CK, Hansen SD, Cobb JA, Burke JE. Development of an inhibitory TTC7B selective nanobody that blocks EFR3 recruitment of PI4KA. bioRxiv. 2025 Jul 31:2025-07. | |
| dc.identifier.uri | https://hdl.handle.net/1828/22883 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Available to the World Wide Web | |
| dc.subject | PI4KA | |
| dc.subject | Structural biology | |
| dc.subject | HDX-MS | |
| dc.subject | Proteins | |
| dc.subject | Phosphoinositides | |
| dc.subject | Cryo-EM | |
| dc.title | Molecular mechanisms involved in the regulation of phosphatidylinositol 4-kinase III α (PI4KIIIα/PI4KA) | |
| dc.type | Thesis |