EASTBIO Effect of molecular crowding on motors and microtubules
Microtubules are long polymers important for cell division, intracellular transport and polarity. Many proteins walk along microtubules and associate with their plus ends. The plus ends act as a platform for signalling and regulatory proteins. An important question is how do motors navigate a crowded microtubule and how do they function at the crowded end of microtubules.
The Welburn lab has previously shown that Kinesin-8 motors are highly processive motors that reach the ends of microtubules and deliver EB and the microtubule depolymerase MCAK to microtubule ends to regulate its length. This process is particularly important to control astral microtubule length and spindle positioning during cell division.
The student will use chemical approaches to functionally derivatise tubulins so that microtubules with obstacles can be generated. Using the unique expertise of the Hulme lab, macrocyclic compounds targeting the maytansine sub-site and selectively targeting the growing end of microtubules will also be synthesized and optimized. Computational approaches will be used to optimize the molecules. The student will first characterise the compounds biophysically with purified tubulin and test its activity on microtubule dynamics and assembly in vitro.
Using a bottom up approach, the student will then determine how molecular crowding (1) on the microtubule lattice affect motor processivity, speed and cooperativity (2) at microtubule ends affect cargo delivery and microtubule dynamics using in vitro reconstitution and biophysics.
This project will give the student opportunities to learn organic chemistry and small molecule synthesis and coupling, protein purification and isolation, in vitro reconstitution approaches using microtubules, single molecule microscopy techniques to image motors and automated image analysis. The development of compounds that target the maytansine sub-site will also represent the development of new tools as plus end markers in systems difficult to modify genetically or transfect.
This project enables a motivated Ph.D. student to apply chemistry, cell biology, biochemistry and in vitro reconstitution assays to investigate the molecular properties of microtubules and develop new tools for study of the cytoskeleton. These results will have strong implications for our understanding of the synthesis of macrocyclic drugs, cytoskeleton biology and chromosome segregation.
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