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Periodic Report Summary 1 - MITDYN (Studies on the role of Plk1 localization and activity in the regulation of microtubule dynamics during mitosis)

Microtubules are long polar polymers composed of alpha- and beta-tubulin. Microtubules switch stochastically between growth and shrinkage, a tightly-controlled process known as dynamic instability that is critical for microtubule function in cellular processes. At the interphase to mitosis transition, the microtubule cytoskeleton undergoes rapid remodeling with an increase in its dynamics parameters, which allows microtubules to rearrange and assemble into a spindle, while also capturing and aligning chromosomes. Regulators of microtubule dynamics increase the catastrophe rate to an estimated two to ten-fold and decrease the rescue rate four-fold. In particular, the Kinesin-13 family members are major microtubule depolymerases that hydrolyze ATP to promote microtubule catastrophe. Importantly, kinesin-13 proteins can also depolymerize taxol-stabilized microtubules and are implicated in the resistance to taxol in cancer cell lines. However they are tightly regulated by intrinsic and extrinsic factors to control chromosome segregation spatially and temporally. Our lab focuses on the kinesin-13, MCAK, as a paradigm for the mechanism and regulation of microtubule depolymerases. MCAK is recruited to the plus tips of microtubules via End-Binding (EB) proteins and to kinetochores through an interaction with Sgo2. At the onset of mitosis, the kinesin-8 Kif18b associates with MCAK and EB1 to generate a powerful microtubule depolymerizing complex and dramatically remodels the microtubule cytoskeleton to allow efficient chromosome capture, alignment and segregation. However, the molecular mechanisms by which these proteins associate and synergize to promote microtubule depolymerization and facilitate timely mitotic progression is unclear.
In this project, we aim to understand the function and role of the Kinesin-8 Kif18b in regulating specifically the Kinesin-13 MCAK function during mitosis and the implication for spindle assembly, positioning and for chromosome segregation. First we are conducting cell biology and biochemistry studies of the Kinesin-8 to understand the molecular basis for the properties of Kif18b and its function in the cell. We are also performing structural studies on the non-motor regions of Kif18b which are essential for targeting to microtubule ends. Reconstitution of a kinesin-8 in vitro and analysis of its interaction with the Kinesin-13 MCAK member at single microtubule ends will complement our structural approach, for which we are expert. The combination of structural, biophysical and cellular studies with aim of reconstituting the biological complexity found at microtubule tips is groundbreaking and will allow us in future studies to understand how the combinatorial associations of microtubule regulators cooperate spatially and temporally to coordinate plus end dynamics.

Reported by

United Kingdom


Life Sciences
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