The Mechanism of Spindle Assembly and Chromosome Alignment

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ABSTRACT Through analyzing the spindle matrix proteome, which we defined in our previous funding periods, we have made a number of exciting observations. Most importantly we have demonstrated that the spindle matrix protein, BuGZ, undergoes oligomerization via phase transition or coacervation to form liquid droplets in vitro mediated in part by the hydrophobic residues found in the intrinsically disorder region of BuGZ. The coacervation activity of BuGZ is essential for assembly of the spindle and its matrix. BuGZ coacervation in vitro as pure protein or in the spindle matrix concentrates tubulin and promotes MT assembly and bundling. Our published and unpublished findings suggest that the interaction and/or coacervation of BuGZ and another spindle assembly factor, TPX2, promotes spindle assembly. Here we propose to use biophysical, biochemical, and cell biological approaches to dissect the molecular mechanism by which these spindle assembly factors synergize to regulate Aurora A activation, microtubule assembly, and kinetochore-microtubule interactions in mitosis.