Mechanisms of assembly and inheritance of yeast septin-containing structures

隔膜蛋白家族的成员在几乎所有真核生物中都存在，通常是以杂寡体的形式存在。 复合体，其适当的组织是其功能所必需的。尽管它的机械细节 它们的作用在很大程度上仍不清楚，Septins参与了各种细胞过程，通常涉及 质膜重塑。扰乱Septin杂低聚物化学计量学的突变或错误调节 是与Septin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。在发芽酵母中，第一次发现了分隔素，异八聚体-其亚单位 其组成与人类间隔蛋白复合体的组成惊人地相似--聚合成排列的细丝 在细胞分裂和形态发生部位。含Septin的细胞结构在分裂分化中的作用 细胞是动态的，在时间和空间调节的组织中经历突然的变化 举止。尚不清楚具有适当排列的Septin亚基的组件如何构建在细胞中， 或者它们在扩散和发展周期中是如何重组的。酵母菌隔膜代表了一种 优雅而强大的系统，用来识别调节这些组织的细胞机制 多亚基大分子组装。 该奖项支持的实验将研究单个Septin蛋白是如何被结合到 根据细胞需求量身定做的不同组件，以及共价修饰和Septin相关的 影响高阶Septin组装的因素。这些研究利用了最近开发的工具来标记 酵母蛋白。其中某些允许用各种功能标签来标记单独的隔膜蛋白 通过细胞分裂和分化进行追踪。其他人则允许纳米级的现场可视化 分辨率，并将被用来精确地确定更高阶组件中的间隔素的组织 在体内，并通过使用超高分辨率光学显微镜的并行方法进行验证。一种遗传方法 将用于确定体内控制Septin动态的细胞因子，特别是Hsp104，a 有望成为治疗由Septin错误组装引起的疾病的新方法的候选药物。

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.