布氏锥虫中动点蛋白和动点蛋白复合物的结构和功能研究

动点是位于染色体着丝粒上的多组分蛋白质超级复合物。它不仅直接维系染色体与纺锤体的衔接，同时调控染色体运动和分离的准确性，在有丝分裂过程中扮演着极其重要的角色。动点介导的纺锤体与染色体连接异常将导致染色体的丢失、易位等，从而使细胞生长失控以及各种癌症的发生。布氏锥虫是导致人的嗜睡病和牲畜的那加那病的病原体。同时它也是一种理想的模式生物。在布氏锥虫中发现的动点蛋白和其它真核生物的动点蛋白在蛋白质序列上没有任何的相似性和保守性，这些发现为动点蛋白的研究开辟了一个全新的有趣的进化研究领域。本项目将围绕布氏锥虫中的动点蛋白和动点蛋白复合物（重点将围绕鉴定出来的与微管相互作用的动点蛋白KKT8、KKT12、KKT16、TCP-1及其可能形成的亚复合物）的结构和功能开展相关的工作。这些研究将有助于我们深入地了解真核生物的动点蛋白及其起源和进化。此外，我们还将筛选优化针对动点蛋白的小分子抑制剂。

Kinetochore is a multicomponent protein supercomplex located at the centromere of chromosome. It plays an extremely important role in mitosis by maintaining directly the connection between chromosome and spindle and regulating the accuracy of chromosome movement and separation. The abnormal connection between spindle and chromosome mediated by kinetochore will lead to the loss and translocation of chromosome, which will eventually result in the uncontrolled cell growth and the occurrence of various cancers. Trypanosoma brucei (T. brucei) is the lethal parasite responsible for sleeping sickness in human and nagana in cattle. It is also an ideal model organism. The kinetochore proteins identified in T. brucei have no sequence similarity and conservation compared with the kinetochore proteins from other eukaryotes. These findings open up a new and interesting field of evolutionary research for kinetochore proteins. In this project, we will investigate the structure and function of kinetochore proteins and protein complexes (emphasizing on the kinetochore proteins KKT8, KKT12, KKT16 and TCP-1, which are identified to interact with microtubules, and the potential subcomplex formed by them) from T. brucei. These studies will strengthen our understanding on kinetochore proteins and their origin and evolution in eukaryotes. In addition, we will screen and optimize the small molecular inhibitors for kinetochore proteins.