The objective of the proposed research is to undertake a detailed structure/function analysis of a longrecognized, but underinvestigated, class of proteins: the phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs). The objective of this proposal is to elucidate the in vivo function of Sec14p-like phosphatidylinositol (PI)/phosphatidylcholine (PC) transfer proteins -- prototypical members of a novel class of signaling molecules. Our data indicate that the yeast PITP (Sec14p) is an essential factor that operates at the interface of phospholipid metabolism and Golgi secretory function. The proposed studies will test specific hypotheses that relate to: (i) how Sec14p recognizes and binds phospholipid ligands, (ii) mechanisms by which the activities of Kes1p, GTPase activating proteins, protein kinases and core components of the membrane trafficking machinery are coordinated in the Golgi secretory program, and (iii) the nature of the lipid signaling and membrane trafficking interface that regulates vesicle budding from Golgi membranes. These studies will clarify key unanswered questions regarding the mechanism of function of the Sec14p itself and the pathway through which Sec14p effects an essential stimulation of yeast Golgi function. The available evidence suggests that PITPs play central, and previously unrecognized, roles in phospholipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, phototransduction, and receptor-mediated signaling. As at least two cases of inherited PITP insufficiency in higher eukaryotes result in neurodegeneration, the proposed studies will provide new and fundamental information that will bear directly on the molecular mechanisms by which PITPs protect the mammalian nervous system from neurodegenerative disease.
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