Phospholipids in Golgi Secretory Function

描述（由申请人提供）： 拟议的研究的目的是进行详细的结构/功能分析的一个长期公认的，但研究不足，一类蛋白质：磷脂酰肌醇/磷脂酰胆碱转移蛋白（PITP）。本提案的目的是阐明Sec 14 p-样磷脂酰肌醇（PI）/磷脂酰胆碱（PC）转移蛋白-一类新型信号分子的原型成员的体内功能。我们的数据表明，酵母PITP（Sec 14 p）是一个重要的因素，在界面上的磷脂代谢和高尔基体分泌功能。拟议的研究将检验与以下方面有关的具体假设：（i）Sec 14 p如何识别和结合磷脂配体，（ii）在高尔基体分泌程序中协调Kes 1 p、GT3活化蛋白、蛋白激酶和膜运输机制的核心组分的活性的机制，以及（iii）调节囊泡从高尔基体膜出芽的脂质信号传导和膜运输界面的性质。这些研究将澄清关于Sec 14 p本身的功能机制和Sec 14 p影响酵母高尔基体功能的重要刺激的途径的关键未回答的问题。 现有的证据表明，PITP发挥中央，以前未被认识到，在磷脂介导的信号转导过程中的作用，接口等不同的细胞过程，如蛋白质分泌，光转导，受体介导的信号。由于高等真核生物中至少有两例遗传性PITP不足导致神经变性，因此拟议的研究将提供新的和基本的信息，这些信息将直接影响PITP保护哺乳动物神经系统免受神经变性疾病的分子机制。

DESCRIPTION (provided by applicant): 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.