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，它自组装成特定的异寡聚复合体，能够聚合形成细丝和其他超分子排列。Septin结构通过与特定的脂类相互作用而与生物膜结合，并参与细胞的区域化和各种膜重塑事件。间隔蛋白在细胞分裂和细胞分化中起着重要的作用。此外，由于间隔蛋白在实体瘤中的表达改变或在白血病中的易位，因此与多种癌症有关。此外，Septins的表达变化与神经病理状况有关，如阿尔茨海默病和帕金森氏病，以及视网膜病变，而SEPT9的突变是遗传性神经痛性肌营养不良(HNA)的原因。然而，人们对控制Septin组织和功能的分子机制知之甚少。进一步的功能表征对于我们理解它们可能的诊断、预后和治疗应用是非常重要的。例如，导致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组装和它们与膜磷脂酰肌醇的相互作用是什么？SEPTIN原位结构的组织结构是什么？Septins的翻译后修饰对其性质有何影响？Septins是如何与其他细胞调节因子和细胞骨架元素相互作用和影响的？我们将使用发芽酵母作为模型系统来解决这些问题。了解在这个真核生物模型中，隔膜蛋白组装是如何被调控的，这可能会为研究异常的隔膜蛋白结构如何导致恶性肿瘤和疾病提供新的见解。

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.