Regulation of intramolecular dynamics, motile properties and intracellular functions of bi-directional kinesin-5 motors

Cell division is driven by a molecular structure, known as the mitotic spindle, which has two opposite poles. Filaments emanate from the two poles and connect at the center of the mitotic spindle. Once the genome has faithfully duplicated, these filaments connect to chromosomes and enable them to segregate to opposite sides that form two new cells. For this chromosome segregation to work effectively, the spindle must elongate dynamically. Spindle assembly and elongation is driven by molecular motors, including kinesin-5, that 'walk' on the spindle filaments via their motor domains. Kinesin-5 motors are essential for life and when their function is inactivated, cell division cannot take place and the cells eventually die. Since some types of cancers cells are enriched in kinesin, it is currently held – and has been shown for some cancers – that drugs targeting kinesin-5 will have therapeutic value in cancer treatment.

The kinesin-5 motors are unique in that they function in complexes with two pairs of motile elements located at opposite ends of the active complex. Due to this structural feature, kinesin-5 motors can simultaneously attach to and walk on two spindle filaments emanating from opposite ends of the mitotic spindle, thereby providing forces that cause the assembly and elongation of the mitotic spindle.

In this project, we will investigate the mechanisms by which kinesin-5 motors perform their functions in spindle assembly and elongation. In our previous research, we found that some kinesin-5 motors work differently from others in that they can move in two directions on the spindle filaments. In this research, we aim to further characterize the differences in motility between the kinesin-5 motors and identify the different parts of the kinesin-5 proteins that are responsible for producing the different modes of activity.

Our mechanistic studies will provide a deeper understanding of the function of the spindle in driving cell division, and how changes in kinesin-5 motor activity enable different spindle behaviors. Our results may also help to understand the altered cell and tissue dynamics that occur in disease states such as cancer and to suggest new strategies for clinical intervention.