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Julie Welburn

Co-workers:

Jovana Deretic, Agata Gluszek, Thibault Legal, Toni McHugh
Welburn Lab website

Structural and cell biology of mitosis, microtubules and motors

Microtubules are dynamic polymers made of tubulin dimers that undergo stochastic switching between growth and shrinkage, marked by catastrophe and rescue events. These highly dynamic microtubule polymers drive the formation and maintenance of the bipolar spindle, kinetochore-microtubule attachments, chromosome oscillations, and chromosome movement and segregation during mitosis. Microtubules in mitosis are tightly regulated by multiple players to allow self- organisation into the mitotic spindle and chromosome alignment and segregation. In particular microtubule motors and proteins that regulate the dynamic ends of microtubules are critical to ensure these processes. They are tightly spatially and temporally regulated by localized mitotic  kinases to fine-tune their activity on microtubules and kinetochores. Work in the lab focuses on the function of kinesin motors, in particular microtubule depolymerases of the kinesin superfamily Kinesin-13 and Kinesin-8 and microtubule stabilizing proteins, that promote microtubule growth. Our goals are to understand how microtubules and their regulatory players mechanistically control the spindle and cell division. We integrate both molecular and cellular approaches to understand the mechanisms underlying faithful mitosis.
 
Recently, we have  focused on the mechanism of the kinesin-13 motor protein MCAK, a potent microtubule depolymerase essential in many cellular processes from mitosis to neuron formation and primary cilia maintenance. The divergent non-motor regions flanking the ATPase domain are critical in regulating  its targeting and activity. However, the molecular basis for the function of the non-motor regions within the context of full-length MCAK is unknown. Here we determine the structure of MCAK motor domain bound to its regulatory C-terminus. Our analysis  reveals that the MCAK C-terminus binds to the motor domain to stabilize MCAK conformation  in solution and is displaced allosterically upon microtubule binding, which allows its robust accumulation at microtubule ends. These results demonstrate that MCAK undergoes long-range conformational changes involving its C-terminus during the soluble to microtubule-bound transition and that the C-terminus-motor interaction represents a structural intermediate  in the catalytic cycle of MCAK. Together, our work reveals intrinsic molecular mechanisms underlying the regulation of kinesin-13 activity.
 

Selected publications:

Ye A., Deretic J., Hoel C.M., Hinman AW., Cimini D., Welburn JPI, Maresca TJ. Aurora A kinase contributes to a pole-based error correction pathway. Current Biology (2015).
Talapatra S., Harker B., Welburn JPI. The C-terminal region of MCAK controls its activity and structure through a major conformational switch. Elife (2015).
Analysis of microtubule dynamic regulators highlights length-dependent anisotropic scaling of spindle shape”. Biology Open. (2014). 3:1217-1223. Young S., Besson S., Welburn JPI.
Analysis of microtubule dynamic regulators highlights length-dependent anisotropic scaling of spindle shape. Biology Open. (2014). 3:1217-1223. Young S., Besson S., Welburn JPI.

 


A. Schematic diagram showing that syntelically attached kinetochores are in close proximity to centrosomelocalized Aurora A. As a result, both Aurora A and B contribute to the destabilization and error correction of
kinetochores close to the poles.
B. Structure of a human motor-CT domain MCAK complex. Kinesin motor domain dimers (cyan and green) bound to the CT domain (yellow, spacefill) of MCAK. ADP is in red.