Mechanisms of assembly and inheritance of yeast septin-containing structures

含有酵母septin的结构的组装和遗传机制

• 批准号: 8333946
• 负责人: MICHAEL A MCMURRAY
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333946
• 关键词: Award; Cell Differentiation process; Cell division; Cell membrane; Cell physiology; Cells; Cellular Structures; Complex; Development; Disease; Equilibrium; Eukaryota; Filament; Genes; Genetic; Human; Imagery; In Situ; Individual; Instruction; Label; Location; Malignant Neoplasms; Methods; Modification; Molecular; Morphogenesis; Mutation; Neurons; Protein Family; Proteins; Resolution; Role; Saccharomyces cerevisiae; Saccharomycetales; Site; Structure; System; Work; Yeasts; hereditary neuropathy; human disease; in vivo; light microscopy; macromolecular assembly; member; nanometer; nanoscale; novel; research study; stoichiometry; tool; ultra high resolution; yeast protein

Members of the septin family of proteins are found in nearly every eukaryote, typically as hetero-oligomeric complexes, the proper organization of which is required for their function. Although the mechanistic details of their roles remain largely unknown, septins participate in a variety of cellular processes, generally involving plasma membrane remodeling. Mutation or misregulation that upsets the stoichiometry of septin heterooligomers is a common feature of septin-associated human diseases, which include cancer and hereditary neuropathies. In budding yeast, where septins were first identified, hetero-octamers - whose subunit composition is strikingly similar to those within human septin complexes - polymerize into filaments arrayed at sites of cell division and morphogenesis. Septin-containing cellular structures in dividing and differentiating cells are dynamic, undergoing abrupt changes in organization in a temporally and spatially regulated manner. It is not known how assemblies with the proper arrangement of septin subunits are built in the cell, or how they are reorganized during cycles of proliferation and development. The yeast septins represent an elegant and powerful system with which to identify cellular mechanisms regulating the organization of these multi-subunit macromolecular assemblies. Experiments supported by this award will examine how individual septin proteins are incorporated into distinct assemblies tailored to cellular demands, and how covalent modifications and septin-associated factors influence higher-order septin assembly. These studies exploit recently-developed tools for labeling of yeast proteins. Certain of these allow individual septins to be marked with a variety of functional tags and tracked through cell division and differentiation. Others allow visualization in situ with nanometer-scale resolution, and will be used to precisely detemiine the organization of septins within higher-order assemblies in vivo, and validated by a parallel method using ultra-high-resolution light microscopy. An genetic approach will be used to identify cellular factors controlling septin dynamics in vivo, with particular focus on Hsp104, a promising candidate for a novel treatment for diseases caused by septin misassembly.

septin蛋白家族的成员几乎存在于每一种真核生物中，通常是异源寡聚体 复合体，其功能需要适当的组织。虽然机械的细节 septins的作用在很大程度上仍然未知，septins参与各种细胞过程，通常涉及 质膜重塑破坏Septin异源寡聚体化学计量的突变或失调 是败血素相关的人类疾病的共同特征，包括癌症和遗传性疾病。 神经病在芽殖酵母中，septins首先被发现，异八聚体-其亚基 组成与人类septin复合物中的那些惊人地相似--排列成细丝排列 在细胞分裂和形态发生的地方。分裂和分化中的含septin的细胞结构 细胞是动态的，在时间和空间调节中经历组织的突然变化 方式目前还不知道如何在细胞中构建具有正确排列的septin亚基的组件， 或者它们在增殖和发展的周期中是如何重组的。酵母胞菌素代表了 优雅而强大的系统，以确定细胞机制调节这些组织 多亚基大分子组装体。 该奖项支持的实验将研究单个Septin蛋白如何被整合到 不同的组装量身定制的细胞需求，以及如何共价修饰和septin相关 影响高阶隔蛋白组装的因素。这些研究利用最近开发的标记工具， 酵母蛋白其中的某些允许用各种功能标签标记单独的隔膜， 通过细胞分裂和分化来追踪。另一些则允许纳米尺度的原位可视化 分辨率，并将用于精确地确定高阶程序集中的septins组织 在体内，并通过使用超高分辨率光学显微镜的平行方法验证。遗传学方法 将被用来确定细胞因子控制septin动力学在体内，特别是对热休克蛋白104， 有希望的候选人的新疗法引起的疾病septin错误组装。