The Yeast Centrosome - Structure Assembly & Function

酵母中心体 - 结构组装

• 批准号: 8668219
• 负责人: MARK WINEY
• 金额: $ 146.06万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668219
• 关键词: Address; Alleles; Architecture; Cell Cycle; Cells; Centrosome; Chromosome Segregation; Chromosome abnormality; Chromosomes; Collaborations; Colorado; Complex; Data; Defect; Developmental Delay Disorders; Disease; Environment; Event; Fluorescence Resonance Energy Transfer; Future; Genomic Instability; Goals; Grant; Homeostasis; Human; In Situ; In Vitro; Individual; Knowledge; Lead; Learning; Malignant Neoplasms; Maps; Measures; Mechanics; Microtubule-Organizing Center; Microtubules; Mitosis; Mitotic Chromosome; Mitotic spindle; Modeling; Molecular; Organelles; Principal Investigator; Program Research Project Grants; Property; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Resources; Roentgen Rays; Rupture; Saccharomyces cerevisiae; Site; Structural Biologist; Structural Models; Structure; Testing; Tubulin; Vertebrates; Washington; Wisconsin; Work; Yeasts; biophysical techniques; chromosome movement; electron tomography; flexibility; in vivo; interdisciplinary approach; interest; metaplastic cell transformation; mutant; nervous system disorder; public health relevance; spindle pole body

DESCRIPTION (provided by applicant): Grant (PPG) will create a collaborative environment to coordinate research on centrosome structure, mechanics, homeostasis and function. Six investigators will study the Saccharomyces cerevisiae centrosome as a model microtubule-organizing center (MTOC) analogous to the vertebrate centrosome, which shares key homologous components and regulators. A centrosome/SPB is the primary microtubule-organizing center of the cell and is critical for bipolar spindle assembly and accurate mitotic chromosome segregation. Centrosome duplication is an essential cell cycle event being the first step in spindle formation; defects in duplication or function lead to genomic instability and cellular transformation. Accurate chromosome segregation depends on both proper regulation of spindle assembly and precise connections between spindle microtubules and chromosomes. The PPG is focused specifically on 10 core SPB components that form the lattice and microtubule nucleation sites including the y-tubulin complexes. These proteins act similarly to the pericentriolar material of vertebrate centrosomes, which is crucial for microtubule nucleation and organization, but poorly understood. We propose to elucidate the molecular architecture of the yeast centrosome and to probe the mechanisms, by which it is assembled, maintained and functions in nucleating microtubules. A multidisciplinary approach examining different aspects of the problem will be coordinated to include: determining how the structure and mechanics of the y-tubulin complex and associated proteins collaborate to accomplish microtubule nucleation; investigating how core SPB components are assembled and how they recruit y-tubulin complexes; identifying the critical intrinsic and extrinsic factors for maintaining homeostasis of this dynamic organelle; solving the atomic structure of SPB components and complexes, and working toward an integrated structural model of the entire SPB core. This PPG builds on existing collaborations between David Agard (UCSF) and Trisha Davis (U. Washington) on g- tubulin complexes, and Ivan Rayment (U. Wisconsin) and Mark Winey (U. Colorado) on core SPB components. These four groups will work together on the 10 proteins. Their projects will profit from structural modeling of the SPB (Andrej Sali, UCSF) and quantifying the mechanical properties of the SPB using biophysical techniques (Chip Asbury, U. Washington). There is tremendous potential to produce an unprecedented molecular description of a centrosome revealing mechanisms of assembly, stability and function. This work will serve as a model for future analysis of the much more complex human centrosome.

描述（由申请人提供）：格兰特（PPG）将创建一个协作环境，以协调中心体结构，力学，稳态和功能的研究。六名研究人员将研究酿酒酵母中心体作为一个模型微管组织中心（MTOC）类似于脊椎动物中心体，共享关键的同源组件和监管机构。中心体/SPB是细胞的主要微管组织中心，并且对于双极纺锤体组装和精确的有丝分裂染色体分离至关重要。中心体复制是细胞周期中重要的事件，是纺锤体形成的第一步;复制或功能缺陷导致基因组不稳定和细胞转化。准确的染色体分离依赖于纺锤体组装的正确调节和纺锤体微管与染色体之间的精确连接。PPG特别关注形成晶格和微管成核位点（包括y-微管蛋白复合物）的10种核心SPB组分。这些蛋白的作用类似于脊椎动物中心体的中心粒周围物质，这对微管成核和组织至关重要，但了解甚少。我们拟阐明酵母中心体的分子结构，并探讨其组装、维持和在成核微管中发挥作用的机制。一个多学科的方法检查不同方面的问题将协调，包括：确定如何结构和力学的y-微管蛋白复合物和相关蛋白质合作，以完成微管成核;调查如何核心SPB组件组装，以及他们如何招募y-微管蛋白复合物;确定关键的内在和外在因素，维持动态细胞器的稳态;解决SPB组分和复合物的原子结构，并致力于整个SPB核心的集成结构模型。这个PPG建立在大卫阿加德（加州大学旧金山分校）和特丽莎戴维斯（美国）之间的现有合作。华盛顿）对g-微管蛋白复合物的研究，和Ivan Rayment（U.威斯康星州）和马克维尼（美国。科罗拉多）的核心SPB组件。这四个小组将共同研究这10种蛋白质。他们的项目将受益于SPB的结构建模（Andrej Sali，UCSF）和使用生物物理技术量化SPB的机械性能（Chip阿斯伯里，U。华盛顿）。有巨大的潜力产生一个前所未有的中心体分子描述揭示组装，稳定性和功能的机制。这项工作将作为未来分析更复杂的人类中心体的模型。