Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis

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DESCRIPTION (provided by applicant): The objective of the proposed research is to undertake a comprehensive functional analysis of an underinvestigated class of proteins: the phosphatidylinositol/ phosphatidylcholine transfer proteins (PITPs). The Sec14-like cabal of the PITP ensemble consists of > 500 proteins, yet remains a poorly studied class of signaling proteins. This is particularly true for multi-domain Sec14-proteins because expression of these proteins is limited to higher eukaryotes and thus less easily amenable to functional analysis using genetic approaches. We recently discovered that Sec14-nodulin and Sec14-GOLD proteins control developmentally regulated pathways for polarized membrane trafficking in Arabidopsis. We will take advantage of the Arabidopsis model to determine how Sec14-nodulin and Sec14-GOLD proteins execute their biological functions. We expect the findings that come from these Arabidopsis studies will translate directly to mammalian systems, and that these studies will clarify essentially uninvestigated questions regarding the mechanism of function of such higher eukaryotic multi-domain Sec14 proteins. From the standpoint of human health, the evidence indicates Sec14-like PITPs regulate the interface between phospholipid-mediated signal transduction processes and diverse cellular processes such as membrane trafficking, actin organization, lipid signaling, receptor-mediated signaling, and neuronal function. As there are several known cases of inherited Sec14-like protein insufficiency in higher eukaryotes that result in neuropathies and carcinomas, the proposed studies will provide new and fundamental information with direct bearing on the molecular mechanisms by which multi-domain Sec14s proteins protect mammals from neurodegenerative and proliferative diseases.