THREE-DIMENSIONAL STRUCTURE AND FUNCTION OF THE MAMMALIAN KINETOCHORE

哺乳动物动粒的三维结构和功能

• 批准号: 7954569
• 负责人: BRUCE F MCEWEN
• 金额: $ 5.59万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954569
• 关键词: Anaphase; Biological; Cell Cycle Checkpoint; Cell division; Cellular biology; Chromosomes; Complex; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; DNA Sequence Rearrangement; Disease; Electron Microscopy; Exhibits; Faculty; Freezing; Functional disorder; Funding; Genomics; Grant; Health; Imagery; Institution; Kinetochores; Lateral; Link; Malignant Neoplasms; Microtubules; Mitosis; Mitotic spindle; Molecular; Nature; Paper; Process; Progress Reports; Radial; Relative (related person); Research; Research Personnel; Resources; Role; Source; Specimen; Spontaneous abortion; Structure; Therapeutic Agents; United States National Institutes of Health; abstracting; electron tomography; flexibility; pressure; segregation; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT: The mammalian kinetochore is a multi-component, proteineous complex whose dysfunction is linked to a number of major health problems including cancer, birth defects, and miscarriages. The kinetochore's essential role in genomic segregation makes it an attractive target for developing chemo-therapeutic agents that inhibit cell division in diseases such as cancer and immuno-proliferative disorders. The kinetochore functions during mitosis include: 1) attaching chromosomes to the mitotic spindle; 2) controlling the dynamics of kinetochore microtubules; 3) generating force for chromosome alignment; and 4) generating a cell cycle checkpoint that delays anaphase onset until all chromosomes are attached to the mitotic spindle and aligned at the spindle equator. Intricate interactions between kinetochores and microtubules (MTs) are essential for all of these vital processes. Despite rapid progress in identifying molecular components of the kinetochore, understanding of the underlying mechanisms of kinetochore function and its interactions with microtubules is just beginning to unfold. This is due in part to the paucity of structural information concerning how different kinetochore molecular components are arrange relative to each other and to attached kinetochore microtubules. The McEwen lab is using electron tomography and serial-section electron microscopy to determine how specific molecular components enable the kinetochore to maintain dynamic attachments to spindle microtubules. Previously, we used electron tomography of high-pressure frozen and freeze-substituted specimens to determine the structure of the kinetochore outer plate and demonstrate that microtubule dynamics is not coordinated or tightly controlled by the kinetochore. These same studies also established that the kinetochore outer plate is the termination point for about 90% of kinetochore microtubules, that the outer plate exhibits a substantial structural rearrangement upon microtubule attachment, and that outer plate forms two distinct attachments to kinetochore microtubules: lateral attachment to the microtubule walls and radial attachments to the microtubules tips. The study was featured as a highlighted paper in the last RVBC progress report. + Dong, Y., K.J. VandenBeldt, X. Meng, A. Khodjakov, and B.F. McEwen (2007) The outer plate in vertebrate kinetochores is a flexible network with multiple microtubule interactions. Nature Cell Biology 9: 516-522. [With cover picture; "Faculty of 1000" recommended].

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要： 哺乳动物动粒是一种多组分的蛋白质复合体，其功能障碍与许多主要的健康问题有关，包括癌症、出生缺陷和流产。 动粒在基因组分离中的重要作用使其成为开发抑制疾病如癌症和免疫增殖性疾病中细胞分裂的化学治疗剂的有吸引力的靶标。 有丝分裂期间的动粒功能包括：1）将染色体附着到有丝分裂纺锤体; 2）控制动粒微管的动力学; 3）产生用于染色体对齐的力;以及4）产生细胞周期检查点，其延迟后期开始，直到所有染色体附着到有丝分裂纺锤体并在纺锤体赤道处对齐。动粒和微管（MT）之间复杂的相互作用是所有这些重要过程所必需的。 尽管在确定动粒的分子组成方面取得了快速进展，但对动粒功能及其与微管相互作用的潜在机制的理解才刚刚开始。 这部分是由于缺乏关于不同的动粒分子组分如何相对于彼此排列和连接的动粒微管的结构信息。 麦克尤恩实验室正在使用电子断层扫描和连续切片电子显微镜来确定特定的分子成分如何使动粒保持与纺锤体微管的动态连接。 以前，我们使用高压冷冻和冷冻替代标本的电子断层扫描，以确定动粒外板的结构，并证明微管动力学不协调或紧密控制的动粒。 这些相同的研究还确定了着丝粒外板是约90%的着丝粒微管的终止点，外板在微管附着时表现出实质性的结构重排，并且外板形成两种不同的着丝粒微管附着：微管壁的侧向附着和微管尖端的径向附着。 该研究在RVBC上一份进度报告中被列为重点论文。 + 董，Y.，K.J. VandenBeldt，X. Meng，中国茶条孢A. Khodjakov和B.F.麦克尤恩（2007）脊椎动物动粒中的外板是一个具有多个微管相互作用的灵活网络。 Nature Cell Biology 9：516-522. [With封面图片;“教师1000”推荐]。