This application is concerned with the structural and functional characterization of the RZZ protein complex, a critical constituent of metazoan kinetochores. The RZZ, a 400-kDa trimer, is named after the initials of its components, Rod, Zwilch and Zw10. The RZZ is implicated in the execution of mitosis, the process of equal partitioning of the genetic material. In mitosis, the sister chromatids attach to spindle microtubules and become aligned at the metaphase plate. This alignment process is orchestrated by the dynamic interaction of microtubules with kinetochores, the site of end-on attachment for microtubules to mitotic chromosomes. By recruiting the minus-end directed microtubule motor dynein, the RZZ complex contributes to form initial, lateral attachments of kinetochores to microtubules. The RZZ is also required for kinetochore recruitment of Mad1 and Mad2, two essential constituents of the spindle assembly checkpoint (SAC). Through biochemical reconstitution and structural methods, we will gain an understanding of the yet unknown organization of the RZZ. We will also develop biochemical assays to probe the interaction of the RZZ with defined kinetochore and SAC components, thus gaining an insight into the role of the RZZ in the larger framework of kinetochore organization and dynamics.
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