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.

中心体是主要且最受欢迎的微管组织中心 （MTOC）在动物细胞中，但在大多数分化的细胞中 （NCMTOCS）重定向MT组织，而不是中心体。纯粹 NCMTOC的多样性反映了各种细胞类型的不同功能， 服务这些角色的MT组件的亚细胞位置和机制。 了解这些NCMTOC的分子结构， 他们采用的MT组件以及它们用于多种细胞类型的功能 它们的服务仍然是细胞生物学和疾病的重要领域。少数 已被解密的NCMTOC揭示了架构和机制 MT组装与它们用于各种细胞类型的功能一样多样化。在 该提案我们扩展了一个项目，以定义核核的功能 通过提供核定位的脂肪体细胞中的NCMTOC，该细胞为细胞提供服务 并且对于逆行内体贩运至关重要，以支持至关重要的分泌 该细胞类型的角色。我们将确定MT的独特分子机制 通过控制MT组装/成核的两个不同蛋白质复合物组装 从这个NCMTOC。具体而言，该建议旨在进一步定义结构 核表面上的脂肪体NCMTOC，并定义 Patronin和Ninein的MT大会以及他们如何与 微管聚合酶Minispindles（MSP）和其他伴侣成核MT。 该项目的结果将是对 脂肪体NCMTOC的分子和生理功能，揭示 涉及蛋白质和过程的潜在新型疾病病因 他们规范。此外，作为分子MT成核范式 独立于广泛的微管成核γ-微管蛋白，我们将 定义至少一种在MTOC上生成MTS的新机制。