Mechanisms of non-centrosomal microtubule-organizing center functions

非中心体微管组织中心功能的机制

• 批准号: 10360430
• 负责人: TIMOTHY L MEGRAW
• 金额: $ 30.36万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360430
• 关键词: Animals; Architecture; Basement membrane; Binding; Biochemistry; Biological Assay; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Centrosome; Collagen; Complex; Development; Disease; Dynein ATPase; Etiology; Fat Body; Generations; Goals; Homeostasis; Knowledge; Liver; Location; Maps; Measures; Membrane Proteins; Microtubule-Organizing Center; Microtubules; Modeling; Molecular; Molecular Structure; Motor; Nature; Nuclear; Organ; Orthologous Gene; Outcome; Physiological; Physiology; Polymerase; Positioning Attribute; Process; Protein Isoforms; Proteins; Radial; Regulation; Role; Structure; Surface; Testing; Vesicle; Work; cell type; frontier; gamma Tubulin; human disease; infancy; ninein; novel; protein complex; recruit; synergism; trafficking

Centrosomes are the major and best-understood microtubule-organizing centers (MTOCs) in animal cells, yet in most differentiated cells non-centrosomal MTOCs (ncMTOCs) redirect MT organization instead of the centrosome. The sheer diversity of ncMTOCs reflects the different functions of various cell types and the subcellular locations and mechanisms of MT assembly that serve those roles. Understanding the molecular architecture of these ncMTOCs, the mechanisms of MT assembly they employ, and the functions they serve to the diverse cell types they serve remains an important frontier in cell biology and disease. The few ncMTOCs that have been deciphered reveal architectures and mechanisms of MT assembly as diverse as the functions they serve for the varied cell types. In this proposal we expand on a project to define the functions of a perinuclear ncMTOC in fat body cells which serves the cell by providing nuclear positioning and is essential for retrograde endosomal trafficking to support the vital secretory roles of this cell type. We will determine the unique molecular mechanisms of MT assembly by two distinct protein complexes that control MT assembly/nucleation from this ncMTOC. Specifically, this proposal aims to further define the structure of the fat body ncMTOC on the nuclear surface, and to define the mechanisms of MT assembly by Patronin and Ninein and how they cooperate with the microtubule polymerase Minispindles (Msps) and other partners to nucleate MTs. The outcomes of this project will be a definitive and novel understanding of the molecular and physiological functions of the fat body ncMTOC, revealing potentially novel disease etiologies for the proteins involved and the processes that they regulate. Moreover, as a molecular MT nucleation paradigm that is independent of the widespread microtubule nucleator gamma-tubulin, we will define at least one new mechanism to generate MTs at MTOCs.

中心体是微管组织的主要中心，也是人们最了解的中心 (MTOCs)在动物细胞中，但在大多数分化的细胞中非中心体MTOCs (NcMTOCs)重定向MT组织，而不是中心体。纯净的 NcMTOCs的多样性反映了不同细胞类型的不同功能和 发挥这些作用的MT组装的亚细胞位置和机制。 了解这些ncMTOCs的分子结构，机制 它们使用的MT组件，以及它们为不同类型的细胞提供的功能 它们所服务的领域仍然是细胞生物学和疾病的重要前沿。为数不多的 已被破译的ncMTOC揭示了 MT组装的多样性与它们为不同类型的细胞所服务的功能一样。在……里面 这项建议我们扩展了一个项目，以定义核周的功能 脂肪体细胞中的ncMTOC，它通过提供核定位来服务于细胞 对于逆行的内体运输是必不可少的，以支持至关重要的分泌物 此细胞类型的角色。我们将确定MT独特的分子机制 由两个控制MT组装/成核的不同蛋白质复合体组装而成 从这个NCMTOC。具体地说，这项提案旨在进一步定义结构 在核表面的脂肪体ncMTOC，并确定的机制 Patronin和Ninein的MT组装以及他们如何与 微管聚合酶小纺锤体(MSPs)和其他伙伴使MT成核。 该项目的成果将是对 脂肪体ncMTOC的分子和生理功能，揭示 涉及的蛋白质和过程的潜在新的疾病病因 他们所监管的。此外，作为一种分子MT成核范式，即 不依赖广泛存在的微管核因子-微管蛋白，我们将 定义至少一种在MTOC生成MTS的新机制。