The objective of the proposed research is to undertake a detailed analysis of an under investigated class of proteins: the phosphatidylinositol (PtdIns/ phosphatidylcholine (PtdCho) transfer proteins (PITPs). To this end, we will primarily employ the prototypical member of the Sec14-superfamily as experimental model. Our data indicate that the yeast PITP (Sec14) is an essential factor that operates at the interface of phospholipid metabolism and Golgi/endosomal membrane trafficking functions. The proposed studies will test specific hypotheses that relate to: (i) how the Sec14-like 'nanoreactor'proteins bind and exchange their lipid ligands, (ii) the mechanisms by which two non-canonical Sec14-like proteins regulate specific steps of lipid metabolism in yeast, and (iii) how the oxysterol binding protein (OSBP)-related Kes1 antagonizes Sec14-dependent PtdIns-4-phosphate signaling in Golgi/endosomal membranes and how this lipid binding protein antagonism is played out in the dual lipid binding properties of these proteins. These studies will clarify key unanswered questions regarding the mechanism of function of the Sec14 itself, the mechanisms by which Sec14-like proteins couple lipid metabolism to PtdIns kinase signaling, and more global ramifications of PITP functional interactions with the oxysterol binding protein family members (ORPs). The available evidence suggests that PITPs and ORPs play central, and previously unrecognized, roles in lipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, photo-transduction, receptor-mediated signaling, cell-cycle control, and basic lipid metabolism. A growing number of inherited neurodegenerative diseases, and diseases of proliferative disorders (e.g. cancer), are attributed to insufficiencies in PITPs and other Sec14-like proteins. Thus, the proposed studies will provide new and fundamental information that bears directly on molecular mechanisms by which PITPs, and Kes1-like OSBPs, regulate signal transduction in eukaryotes and protect mammals from diseases of deranged cell proliferation and neurodegeneration.
Neurodegenerative disorders and cancer are two examples of pathological states where deficiencies in cellular signaling processes result in human disease. The former are a result of premature cell death, while the latter results from inappropriate cell growth. The proposed studies will help define the mechanisms by which lipid signaling pathways are regulated by a novel class of proteins - the Sec14- like PITPs. Since the pathways to be studied are of direct relevance to neurodegenerative diseases and cancer, it is hoped the new and fundamental information that will derive from these studies will instruct development of new therapies for these disorders.
|Roy, Kevin R; Smith, Justin D; Vonesch, Sibylle C et al. (2018) Multiplexed precision genome editing with trackable genomic barcodes in yeast. Nat Biotechnol 36:512-520|
|Eisenberg-Bord, Michal; Mari, Muriel; Weill, Uri et al. (2018) Identification of seipin-linked factors that act as determinants of a lipid droplet subpopulation. J Cell Biol 217:269-282|
|Pries, Verena; Nöcker, Christina; Khan, Danish et al. (2018) Target Identification and Mechanism of Action of Picolinamide and Benzamide Chemotypes with Antifungal Properties. Cell Chem Biol 25:279-290.e7|
|Blank, Heidi M; Perez, Ricardo; He, Chong et al. (2017) Translational control of lipogenic enzymes in the cell cycle of synchronous, growing yeast cells. EMBO J 36:487-502|
|Tripathi, Ashutosh; Bankaitis, Vytas A (2017) Molecular Docking: From Lock and Key to Combination Lock. J Mol Med Clin Appl 2:|
|Huang, Jin; Ghosh, Ratna; Bankaitis, Vytas A (2016) Sec14-like phosphatidylinositol transfer proteins and the biological landscape of phosphoinositide signaling in plants. Biochim Biophys Acta 1861:1352-1364|
|Huang, Jin; Ghosh, Ratna; Tripathi, Ashutosh et al. (2016) Two-ligand priming mechanism for potentiated phosphoinositide synthesis is an evolutionarily conserved feature of Sec14-like phosphatidylinositol and phosphatidylcholine exchange proteins. Mol Biol Cell 27:2317-30|
|Khan, Danish; McGrath, Kaitlyn R; Dorosheva, Oleksandra et al. (2016) Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors. J Lipid Res 57:650-62|
|McDermott, Mark I; Mousley, Carl J (2016) Lipid transfer proteins and the tuning of compartmental identity in the Golgi apparatus. Chem Phys Lipids 200:42-61|
|Ghosh, Ratna; de Campos, Marília K F; Huang, Jin et al. (2015) Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis. Mol Biol Cell 26:1764-81|
Showing the most recent 10 out of 44 publications