Neuronal Ykt6 Protein Interactions and Targeting

神经元 Ykt6 蛋白相互作用和靶向

• 批准号: 6790674
• 负责人: JESSE C HAY
• 金额: $ 1.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-13 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790674
• 关键词: immunoelectron microscopy; intracellular transport; laboratory mouse; laboratory rabbit; laboratory rat; mass spectrometry; membrane proteins; nerve /myelin protein; protein protein interaction; protein transport; yeast two hybrid system

DESCRIPTION (provided by applicant): SNAP receptor (SNARE) proteins catalyze biological membrane fusion and contribute to the fidelity of intracellular membrane traffic - they are perhaps the most fundamental determinant of an organelle's trafficking in the cell. The yeast prenylated SNARE ykt6p appears to have multiple functions in the constitutive secretory pathway. Unexpectedly, our results demonstrate that mammalian ykt6 does not have the characteristics of a SNARE for constitutive secretion, as it is expressed predominantly in neurons. Furthermore, membrane bound rat ykt6 localizes to unique cytoplasmic vesicular structures that do not overlap appreciably with recognized organelles of the secretory or endosomal systems. This proposal aims to dramatically advance our understanding of neuronal ykt6 and the specialized transport process(es) in which it participates. Our guiding hypothesis is that rat ykt6 is involved in the trafficking of a highly specialized transport organelle containing cargo that is important for aspects of neuronal function. The specific aims are: 1. Test the hypothesis that ykt6 interacts with a unique subset of neuronal SNAREs and other membrane and cytosolic proteins. 2. Test the hypothesis that ykt6 is localized to a specialized transport compartment containing cargo relevant to neuronal function. 3. Test the hypothesis that the NT domain targets ykt6 to its specialized location by binding to a specific membrane receptor. 4. Test the hypothesis that cytosolic ykt6 SNARE interactions are autoinhibited by cooperation between the NT domain and prenyl group(s). These studies will dramatically advance our understanding of membrane trafficking in neurons, and highlight underlying processes that may contribute to human disease. Many of the SNARE regulatory principles discovered in this work will be applicable to SNARE function at multiple membrane transport steps. Importantly, ykt6 is a prenyl protein that is predicted to be modified by protein farnesyltransferase. There is currently little information about the function of farnesylated proteins not involved in cell proliferation. Since many of the most promising new cancer treatments use drugs to inhibit protein farnesyltransferase, it is essential to understand the major metabolic pathways affected when protein farnesylation is stopped. To understand and potentially compensate for the unintended consequences of these drugs in neurons, it is essential to understand the function of the ykt6 membrane transport pathway.

描述（由申请人提供）： SNAP受体（SNARE）蛋白会催化生物膜融合，并有助于细胞内膜交通的保真度 - 它们可能是细胞器在细胞中运输的最基本决定因素。酵母前的SNARE YKT6P似乎在本构分泌途径中具有多个功能。出乎意料的是，我们的结果表明，哺乳动物Ykt6没有构成分泌的圈套的特征，因为它主要在神经元中表达。此外，膜结合的大鼠YKT6定位于独特的细胞质囊泡结构，这些结构与分泌或内体系统的公认细胞器不会显着重叠。该建议旨在极大地提高我们对神经元YKT6及其参与的专业运输过程（ES）的理解。我们的指导假设是，大鼠YKT6参与了贩运高度专业化的运输细胞器，该运输有机体包含货物，这对于神经元功能方面很重要。具体目的是：1。检验YKT6与神经元幼虫的独特子集以及其他膜和胞质蛋白相互作用的假设。 2。检验YKT6定位于包含与神经元功能相关的货物的专门运输室的假设。 3。检验以下假设：NT域通过与特定的膜受体结合，将YKT6靶向其专业位置。 4。检验以下假设：胞质Ykt6 snare相互作用是通过NT结构域与蛋白酶组之间的合作自身抑制的。这些研究将极大地提高我们对神经元中膜运输的理解，并突出可能导致人类疾病的基本过程。在这项工作中发现的许多圈套监管原则将适用于在多个膜运输步骤中的圈圈功能。重要的是，YKT6是一种蛋白质蛋白，预计将通过蛋白Farneyltransferase修饰。目前，关于不涉及细胞增殖的Farnesylation蛋白功能的功能的信息很少。由于许多最有前途的新癌症治疗方法都使用药物抑制蛋白质法尼基转移酶，因此必须了解停止蛋白质法尼化时影响的主要代谢途径。要了解并有可能补偿这些药物在神经元中的意外后果，必须了解YKT6膜传输途径的功能。