Abstract
ABSTRACTKinesin-13 motors regulate precise microtubule dynamics and limit microtubule length throughout metazoans by depolymerizing microtubule ends. Recently, the kinesin-13 motor family member MCAK (also known Kif2C) has been proposed to undergo large conformational changes during its catalytic cycle, as it switches from being in solution to being bound to microtubules. Here, we reveal that MCAK has a compact conformation in solution through crosslinking and electron microscopy experiments. When MCAK is bound to the microtubule ends, it adopts an extended conformation with the N-terminus and neck region of MCAK interacting with the microtubule. Interestingly, the region of MCAK that interacts with the microtubule is the region phosphorylated by Aurora B and contains an end binding (EB) protein-binding motif. The level of phosphorylation of the N-terminus results in a graded microtubule depolymerase activity. Here, we show that the N-terminus of MCAK forms a platform to integrate Aurora B kinase downstream signals and in response fine-tunes its depolymerase activity during mitosis. We propose that this allosteric control mechanism allows decoupling of the N-terminus from the motor domain of MCAK to allow MCAK depolymerase activity at kinetochores.
Highlights
Regulation of microtubule length is key throughout eukaryotes
We demonstrate that full-length MCAK has a compact conformation in solution and becomes extended when bound to microtubules
Overall we show that rather than just inhibiting it, Aurora B fine-tunes the activity of MCAK activity to provide graded levels of microtubule depolymerase activity in the cell
Summary
Regulation of microtubule length is key throughout eukaryotes. Notably, the kinesin-13 family members are potent microtubule depolymerases, which destabilize microtubule ends to promote catastrophe (Walczak et al, 2013). The activity of MCAK is inhibited by Aurora B kinase, through phosphorylation on multiple amino acids within its N-terminus (Andrews et al, 2004; Lan et al, 2004). Aurora B kinase phosphorylation of the Nterminus of MCAK inhibits its microtubule depolymerase activity in vitro in the absence of EB proteins (Lan et al, 2004), the mechanism is unclear.
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