dc.contributor.author | Pietrangelo, Antonietta | |
dc.date.accessioned | 2019-11-28T15:10:22Z | |
dc.date.available | 2019-11-28T15:10:22Z | |
dc.date.issued | 2019-11-28T15:10:22Z | |
dc.identifier.uri | http://hdl.handle.net/10222/76670 | |
dc.description.abstract | Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a 12-member family of mammalian lipid binding and transport proteins with variable tissue expression patterns and ligand affinities. The common feature of the ORP family is an OSBP-homology domain that binds sterol and/or phospholipid ligands, and additional domains involved in membrane-specific interactions that confer a complex suite of organelle-specific ORP functions. The focus of this dissertation is the OSBP paralog ORP4, which is a sterol and phosphatidylinositol-4-phosphate (PI(4)P) binding protein enriched in the brain, testes and retina. In addition to the ligand binding domain, full-length ORP4 (ORP4L) contains an FFAT motif and PH domain that recognize the resident ER protein VAP and PI(4)P, respectively. The PH domain is truncated and absent in medium (ORP4M) and short (ORP4S) isoforms, respectively. While ORP4 levels are elevated in metastatic cancers and known antineoplastic drugs target ORP4 by competitive inhibition, the primary cellular function of ORP4 remains elusive. This research provides evidence that ORP4 is a phospho-regulated lipid binding protein required for cell growth, likely through regulation of trans-Golgi network (TGN) morphology. ORP4 localized to the TGN in an OSBP- and PI(4)P-dependent manner independently of sterol-binding, and ORP4 depletion caused dispersion of the TGN and reduced cis/medial-Golgi PI(4)P levels. ORP4 membrane associations are controlled by ligand-binding and protein-protein interactions, both of which are in turn regulated by phosphorylation of ORP4 at a previously uninvestigated tract of serine residues in the ligand-binding domain. | en_US |
dc.language.iso | en | en_US |
dc.subject | Intracellular lipid transport | en_US |
dc.subject | Cell biology | en_US |
dc.title | ORP4L IS A PHOSPHO-REGULATED LIPID BINDING PROTEIN REQUIRED FOR CELL GROWTH AND MAINTENANCE OF TGN MORPHOLOGY | en_US |
dc.date.defence | 2018-03-20 | |
dc.contributor.department | Department of Biochemistry & Molecular Biology | en_US |
dc.contributor.degree | Doctor of Philosophy | en_US |
dc.contributor.external-examiner | Dr. Christopher Beh | en_US |
dc.contributor.graduate-coordinator | Dr. Jan Rainey | en_US |
dc.contributor.thesis-reader | Dr. Barbara Karten | en_US |
dc.contributor.thesis-reader | Dr. Graham Dellaire | en_US |
dc.contributor.thesis-reader | Dr. Petra Kienesberger | en_US |
dc.contributor.thesis-supervisor | Dr. Neale Ridgway | en_US |
dc.contributor.ethics-approval | Not Applicable | en_US |
dc.contributor.manuscripts | Not Applicable | en_US |
dc.contributor.copyright-release | Yes | en_US |