Septin Filaments: Architecture, Assembly and Regulation

Septin 细丝：架构、组装和调节

• 批准号: 8600295
• 负责人: Eva Nogales
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600295
• 关键词: Address; Affect; Alzheimer' s Disease; Architecture; Binding; Biochemical; Biological; Biological Models; Cell division; Cell physiology; Complex; Cytoskeleton; Data; Diagnostic; Diffusion; Disease; Elements; Event; Family; Filament; GTP-Binding Proteins; Goals; Hereditary Neuralgic Amyotrophy; Imagery; In Situ; Link; Lipids; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Meiosis; Membrane; Mitotic; Modeling; Modification; Molecular; Molecular Models; Mutation; Nature; Neck; Organism; Parkinson Disease; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Polymers; Post-Translational Protein Processing; Property; Protein Isoforms; Proteins; RNA Splicing; Regulation; Reproduction spores; Retinal Diseases; Role; Saccharomycetales; Signal Transduction; Solid Neoplasm; Structure; System; Testing; Therapeutic; Up-Regulation; Variant; Yeasts; base; combinatorial; electron tomography; in vivo; insight; leukemia; malignant breast neoplasm; molecular modeling; mutant; prognostic; public health relevance; research study; self assembly; tumor

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.

描述（由申请人提供）： Septin 是 GTP 结合蛋白的保守家族，其自组装成特定的异源寡聚复合物，该复合物能够聚合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结合，并参与细胞区室化和各种膜重塑事件。脓毒蛋白在细胞分裂和细胞分化中发挥着多种功能作用。此外，脓毒蛋白在实体瘤中表达的改变或在白血病中的易位已与多种癌症相关。此外，septins 的表达变化与阿尔茨海默病和帕金森病以及视网膜病等神经病理学疾病有关，而 SEPT9 的突变是遗传性神经痛性肌萎缩症 (HNA) 的原因。然而，人们对控制脓毒蛋白组织和功能的分子机制知之甚少。脓毒症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，不同septin形式之间相互作用的本质是什么，从而产生具有不同功能特性的聚合物？隔膜组装及其与膜磷酸肌醇的相互作用之间有什么相互作用？脓毒症结构的原位组织是怎样的？脓毒症经历的翻译后修饰如何影响其特性？脓毒症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。了解在该模型真核生物中如何调节隔膜组装可能会提供关于异常隔膜结构如何导致恶性肿瘤和疾病的新见解。