Septin Filaments: Architecture, Assembly and Regulation

描述（由申请人提供）：Septins是一个保守的GTP结合蛋白家族，其自组装成定义的异源寡聚复合物，能够形成细丝和其他超分子排列。Septin结构通过与特定脂质相互作用而与生物膜相关联，并且参与细胞区室化和各种膜重塑事件。细胞分裂素在细胞分裂中是必需的，在细胞分裂中它们发挥许多功能性作用，以及在细胞分化中。此外，细胞分裂素已经基于其在实体瘤中的表达改变或在白血病中的易位而与多种癌症相关。此外，septins中的表达变化与神经病理学病症如阿尔茨海默病和帕金森病以及视网膜病有关，并且SEPT9中的突变是遗传性神经痛性肌萎缩（HNA）的原因。然而，我们对septin组织和功能的分子机制知之甚少。septins的进一步功能表征对于我们理解其可能的诊断、预后和治疗应用显然至关重要。例如，产生具有不同功能特性的聚合物的不同septin形式之间的相互作用的性质是什么？Septin组装及其与膜磷酸肌醇的相互作用之间的相互作用是什么？原位septin结构的组织是什么？septins所经历的翻译后修饰如何影响其性质？septins如何与其他细胞调节因子和细胞骨架元件相互作用并影响它们？我们将使用芽殖酵母作为模型系统来解决这些问题。了解septin组装如何在该模型真核生物中调节，可能会提供有关异常septin结构如何导致恶性肿瘤和疾病的新见解。

DESCRIPTION (provided by applicant): Septins are a conserved family of GTP-binding proteins that self-assemble into defined hetero-oligomeric complexes that are able to polymerize to form filaments and other supramolecular arrangements. Septin structures associate with biological membranes by interacting with specific lipids, and are involved in cellular compartmentalization and a variety of membrane remodeling events. Septins are essential in cell division, where they play a number of functional roles, as well as in cellular differentiation Furthermore, septins have been associated with a variety of cancers on the basis of alterations of their expression in solid tumors or translocations in leukemias. Also, expression changes in septins have been implicated in neuropathological conditions, such as Alzheimer's and Parkinson's disease, as well as retinopathies, and mutations in SEPT9 are the cause of hereditary neuralgic amyotrophy (HNA). Yet, little is known about the molecular mechanisms that govern septin organization and function. Further functional characterization of septins is clearly crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications. For example, what is the nature of the interactions among different septin forms that give rise to polymers with different functional properties? What is the interplay between septin assembly and their interaction with membrane phosphoinositides? What is the organization of septin structures in situ? How do the post- translational modifications that septins undergo influence their properties? How do septins interact with and affect other cellular regulators and cytoskeletal elements? We will address these questions using budding yeast as a model system. Understanding how septin assembly is regulated in this model eukaryotic organism may offer new insights about how aberrant septin structures contribute to malignancy and disease.