Microtubule Structure and Interactions

Microtubules are cylindrical polymers found in every eukaryotic cell. They have a unique helical structure that has implications at both the cellular level, in terms of the functions they perform, and at the multi-cellular level, such as determining the left-right symmetry in plants. We are interested in the molecular basis for this structure, and through the combination of an atomically-detailed model for a microtubule and novel large scale computational techniques to calculate electrostatic interactions, we are able to explain the observed microtubule structure. Based on the lateral interactions between protofilaments, we have determined that B lattice is the most favourable configuration. Further, we find that these lateral bonds are significantly weaker than the longitudinal bonds along protofilaments which can explain observations of microtubule disassembly and may serve as another step toward understanding the basis for dynamic instability.

Dynamic instability can be directly controlled by microtubule associated proteins like tau that bind to and stabilize microtubules. Various isoforms of tau include a three to four 18-residue microtubule binding repeat separated by 13-14 residue inter-repeats. There has been a significant amount of experimental work on tau since it is a factor in Alzheimer's disease, however once again the molecular details of its interaction with the microtubule is not known. Using a reductionist strategy of separating the repeats, simulating and docking them individually we have produced a viable binding model for tau . We find that repeats 2 and 3 bind to α-tubulin near the flexible C-terminus while repeats 1 and 4 bind to β-tubulin. Based on the inter-repeat sequences, we find that tau can link together 2 or 3 protofilaments as shown in the figure below. This model is currently being tested experimentally.