Phospholipids in Golgi Secretory Function

描述(由申请人提供)： 这项拟议研究的目的是对一类被广泛认知但未被研究的蛋白质：磷脂酰肌醇/磷脂酰胆碱转移蛋白(PITPs)进行详细的结构/功能分析。这项建议的目的是阐明Sec14p样磷脂酰肌醇(PI)/磷脂酰胆碱(PC)转运蛋白的体内功能--一类新的信号分子的原型成员。我们的数据表明，酵母PITP(Sec14p)是一个在磷脂代谢和高尔基体分泌功能的交界处起作用的重要因子。拟议中的研究将检验与以下相关的特定假设：(I)Sec14p如何识别和结合磷脂配体；(Ii)在高尔基体分泌程序中Kes1p、GTPase激活蛋白、蛋白激酶和膜运输机制核心组件的活动如何协调的机制；以及(Iii)调节高尔基体膜囊泡萌发的脂信号和膜运输界面的性质。这些研究将澄清有关Sec14p本身的功能机制以及Sec14p对酵母高尔基体功能的重要刺激途径的关键未解问题。 现有证据表明，PITPs在磷脂介导的信号转导过程中扮演着重要的角色，而磷脂介导的信号转导过程与蛋白质分泌、光转导和受体介导的信号转导等不同的细胞过程相互作用。由于在高等真核生物中至少有两例遗传性PITP缺乏会导致神经变性，拟议中的研究将提供直接与PITP保护哺乳动物神经系统免受神经退行性疾病影响的分子机制相关的新的基本信息。

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.