Biomolecular motors are fascinating nanomachines that perform mechanical duties in the cell. Understanding their function, performance and properties has many applications for Engineering such as the development and optimization of synthetic molecular motors for nanotechnology or therapeutic interventions. Kinesins are motors that hydrolyze ATP to produce force and movement of cargos along microtubule tracks in a wide range of cellular processes. Typically, they dimerize with two ATPase domains at one end of the motor separated by coiled-coils of varying length and a cargo adaptor at the other end. These molecular motors are used as a paradigm for understanding nanomachines across physics, engineering and biology. Many of these motors are essential for mitotic spindle architecture and chromosome segregation. In this project, the student will examine how the properties of motors can influence the outcome of cell division- studying CENP-E, the largest motor in the human kinesin family. CENP-E captures of unattached kinetochores at mitotic onset, promotes the alignment of chromosomes and play a role in organizing the central spindle.
They will study how the length, composition and structure of the coiled-coil domain of CENP-E affects coupling of the cargo to the microtubule track and transport. It is currently unclear whether the long coiled-coil acts as a long-range tether to maximize cargo capture and motor cooperation to transport micrometer-sized cargos or whether the length and properties of the coiled-coil domain are not important.
The student will use optical tweezers to measure the compliance of the motor under load. They will analyze how the length and flexible regions containing the coiled-coils within the stalk contribute to motor activity and properties using single molecule reconstitution and fluorescence imaging. Using de novo protein design and computational approaches, they will alter the structure of coiled-coils to increase rigidity and analyze how motor efficiency is affected. Finally, the student will examine how the composition of the coiled-coil domain affects the mitotic activities of the CENPE motor in cells. From these data, the student will build a mathematical model defining the role of coiled-coil compliance in mediating correct chromosome segregation.
The successful candidate will be exposed to multidisciplinary aspects of the project, all of which pose fascinating opportunities for novel discoveries. These results will have strong implications for our understanding of nanomotor design, cellular transport and bioengineering.
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