Regulation of mitosis by kinetochore-dependent mechanisms

通过着丝粒依赖性机制调节有丝分裂

• 批准号: 268663799
• 负责人: Privatdozent Dr. Johannes Lechner
• 金额: --
• 依托单位: Biochemie-Zentrum (BZH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268663799?language=en
• 关键词: Regulation; mitosis; kinetochore; dependent; mechanisms

Regulation of mitosis by kinetochore-dependent mechanisms The S. cerevisiae CLASP, Stu1, orchestrates mitosis by localizing to microtubules and (via its first TOGL domain) to kinetochores in a phase-dependent manner. In metaphase Stu1 localizes to kinetochores and stabilizes kinetochore microtubules in a tension-dependent manner. Furthermore, Stu1 localizes to the lattice of interpolar microtubules and stabilizes the metaphase spindle via the activity of its second TOGL domain and most likely by crosslinking the interpolar microtubules. In anaphase Stu1 dissociates from kinetochores and thus possibly allows the shortening of kinetochore microtubules typical for anaphase A. Stu1 also dissociates from the MT lattice and localizes to the spindle midzone. This still allows microtubule stabilization via the second TOGL domain and most likely alleviates microtubule crosslinking to allow gliding in anaphase. In prometaphase Stu1 gets sequestered at unattached kinetochores. This prevents precocious spindle formation and possibly facilitates capturing of these kinetochores. The dependencies of the Stu1 localization to unattached kinetochores are reminiscent of those that facilitate the localization of spindle assembly checkpoint (SAC) proteins at unattached kinetochores. Moreover Stu1 interacts with the SAC protein Mad1 via the first TOGL domain. In the future we plan to investigate the principles of Stu1 localization: 1) The regulation of kinetochore and microtubule localization in metaphase versus anaphase. 2) The identification of the kinetochore proteins that interact with the first TOGL domain of Stu1. 3) The substrates and phosphorylation sites of the protein kinase Mps1 that is essential for the sequestering of Stu1 at unattached kinetochores. 4) The mechanism that leads to the sequestering effect at unattached kinetochores (induction of a conformational change?). Furthermore we plan to investigate the manifested and putative roles of Stu1 in mitosis: 1) The mechanism that facilitates stabilization of kinetochore microtubules when Stu1 localizes to metaphase kinetochores. 2) The mechanism by which Stu1 promotes capturing of unattached kinetochores. 3) The role of the Stu1-Mad1 interaction.

通过动力学依赖性机制调节有丝分裂的酿酒酵母扣，Stu1，通过将其定位到微管来调节有丝分裂，并以相位依赖性方式（通过其第一个Togl结构域）与动脉化合物。在中期stu1中，stu1定位于动力学，并以张力依赖性方式稳定动力学微管。此外，Stu1定位于近极微管的晶格，并通过其第二个TOGL域的活性稳定中期纺锤体，并且最有可能通过交联近极微管。在后期中，Stu1从动力学上解离，因此可能允许典型的A. STU1缩短动力学微管。这仍然允许微管通过第二个TOGL结构域稳定，并且很可能会减轻微管的交联以使其在后期滑行。在Prometathase中，Stu1在未连接的动物学上被隔离。这样可以防止早熟的纺锤体形成，并可能有助于捕获这些动力学。 STU1定位对未连接的动物学的依赖性让人联想到那些促进纺锤体组装检查点（SAC）蛋白在未连接的动脉化学上的定位的依赖性。此外，Stu1通过第一个Togl域与SAC蛋白MAD1相互作用。将来，我们计划研究Stu1定位的原理：1）在中期与后期中的动元和微管定位的调节。 2）与Stu1的第一个TOGL结构域相互作用的动力学蛋白的鉴定。 3）蛋白激酶MPS1的底物和磷酸化位点对于在未连接的动物学上隔离stu1至关重要。 4）导致未连接动物学上隔离效果的机制（构象变化的诱导？）。此外，我们计划研究Stu1在有丝分裂中的明显和推定的作用：1）当STU1定位于中期动物学上时，促进动型微管稳定的机制。 2）Stu1促进捕获未连接的动物学的机制。 3）Stu1-Mad1相互作用的作用。