Mechanism of molecular motors in chromosome segregation
Mitosis is a highly regulated process that allows equal distribution of the genetic material to the daughter cells. The mitotic spindle is a bipolar structure composed of highly dynamic microtubule polymers. The formation and maintenance of the bipolar spindle and chromosome alignement and segregation during mitosis are critical to maintaining genomic integrity. Several of the mitotic microtubule-associated proteins are key to controlling these processes and therefore prime candidates as anti-cancer drug targets.
Our goal is to define how 1) microtubule motors transport and cooperate with their cargos to ultimately build the mitotic spindle and align chromosomes 2) chromosomes move along the spindle and segregate, using a holistic mechanistic approach ranging from structural biology to single molecule imaging and quantitative cell biology.
Using biochemistry and structural biology, we study the architecture of cell cycle complexes, while cell biology approaches give us a cellular context to understand how molecular machines work. We have already published exciting insights into mechanisms and regulation of mitotic microtubule-associated protein complexes using combined structural, biochemical, and cell biological approaches.
Several of the mitotic microtubule-associated proteins termed kinesins are key to controlling these processes and therefore prime candidates as anti-cancer drug targets. While the majority of kinesin proteins are microtubule-based motors, the kinesin-13 family members are microtubule depolymerizing enzymes that are major mechanistic players in spindle assembly and chromosome movement.
Our recent work reveals new structural and biochemical insights into how MCAK structure (Talpatra et al, Elife, 2015). We show that the C-terminus interacts with the motor in solution and needs to be displaced for MCAK to bind microtubules. Both the C-termini of tubulin and MCAK are essential for targeting to the plus ends and hence efifcient function.
A. Structure of the C-terminus of MCAK bound to the motor. B Alignment of the conserved interacting tail region across species. The essential amino acids supporting the interaction are in green.