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: 10551211
• 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/10551211
• 关键词: Animals; Architecture; Basement membrane; Binding; Biochemistry; Biological Assay; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Centrosome; Collagen; Complex; Cytoskeleton; Development; Disease; Dynein ATPase; Endosomes; 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; Printing; Process; Protein Isoforms; Proteins; Radial; Regulation; Role; Structure; Surface; Testing; Tubulin; 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和最好的理解中心 （MTOC）在动物细胞中，但在大多数分化的细胞中， （ncMTOC）重定向MT组织而不是中心体。庞大 ncMTOC的多样性反映了各种细胞类型的不同功能， 亚细胞的位置和机制的MT组装，服务于这些角色。 了解这些ncMTOC的分子结构， 它们使用的MT组装，以及它们对不同细胞类型的功能 仍然是细胞生物学和疾病的重要前沿。为数不多 已经破译的ncMTOC揭示了 MT的组装与它们为不同细胞类型服务的功能一样多样。在 这个建议，我们扩大了一个项目，以确定功能的核周 脂肪体细胞中的ncMTOC，通过提供核定位为细胞服务 并且对于逆行性内体运输以支持重要的分泌性 这类细胞的作用。我们将确定MT独特的分子机制 通过两种不同的蛋白质复合物组装，控制MT组装/成核 从这个ncMTOC。具体而言，本建议旨在进一步界定 的脂肪体ncMTOC的核表面上，并定义的机制， 由Patronin和Ninein组装MT，以及它们如何与 微管聚合酶Minispeptide（Msps）和其他伙伴使MT成核。 该项目的成果将是对这一问题的明确和新颖的理解。 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学 他们监管。此外，作为分子MT成核范例， 独立于广泛分布的微管成核剂γ-微管蛋白，我们将 定义至少一个新机制，以在MTOC生成MT。