Regulatory switching of a microtubule motor-scaffold complex

About the project

About the Project A 2027 Crick PhD project with Sami Chaaban. Project background and description To divide successfully, a cell must build a highly organised microtubule structure, use it to position the division site, and then remodel it as the two daughter cells separate. Although many of the proteins involved have been identified, we still do not understand how their activities are coordinated to generate the correct architecture at the correct time. Microtubule-based motors are central to this process, but the mechanisms that regulate their activity during cell division remain poorly understood. This project will investigate how kinesin motors organise microtubules and position regulatory proteins during cell division. Although kinesins are often viewed primarily as transport motors, they can also control microtubule overlap, bundling and the local accumulation of protein complexes. The student will determine how interactions with regulatory partners switch kinesins between different functional states and how these changes contribute to the formation of specialised microtubule structures. Using biochemical reconstitution and advanced fluorescence microscopy, the student will observe individual motor complexes interacting with microtubules. These experiments will reveal how regulatory partners influence microtubule binding, directional movement, spatial accumulation and bundling. Engineered protein variants will help distinguish changes in motor conformation from effects caused by oligomerisation, cooperative binding or microtubule geometry. Cryo-electron microscopy will be a major component of the project. The student will learn to prepare structurally defined motor–microtubule assemblies and develop strategies for imaging large, flexible and compositionally heterogeneous protein complexes. Modern computational approaches will then be used to separate distinct conformational states and determine how regulatory interactions reshape the motor complex. These structures will be integrated with the single-molecule measurements to explain how molecular-scale changes control movement and microtubule organisation. Key mechanistic predictions will subsequently be tested in mammalian cells. The project will therefore provide broad training in protein biochemistry, biochemical reconstitution, advanced fluorescence microscopy, computational and quantitative image analysis, structural biology and mammalian cell biology. Candidate background This project would suit candidates with backgrounds in biochemistry, molecular biology, biophysics, structural biology, or a related discipline. Previous experience with recombinant proteins, microscopy or programming would be useful but is not essential. The strongest candidates will be curious about mechanism, willing to work across disciplines and comfortable refining experiments when complex molecular systems behave unexpectedly. Lab-specific question Describe an example from your research experience or studies where understanding a protein’s structure helped explain its function – or left an important question unanswered. How could this inform your approach to studying molecular motors in our lab?

Research areas