The goal of this proposal is to explore further the interaction between microtubules (MTs) and microtubule-associated proteins (MAPs), particularly the ability of certain MAPs to alter the mechanical properties of MTs. It is possible that one of the key functions of MAP binding is to produce concomitant changes in MT stiffness, affecting neuronal development (MAP2 and Tau) or mitotic processes (MAP4), and there is preliminary evidence that MAP binding does result in an increase of MT stiffness. Details of how MAP binding changes MT mechanical properties, and how MAP phosphorylation alters such effects, are potentially useful in understanding certain neuronal diseases like Alzheimer's disease (where infected patients exhibit a hyperphosphorylated form of Tau), and may also help understand certain details of mitosis, during which MAP4's state of phosphorylation is changed by MPF. To accurately measure MT stiffness, a state-of-the-art dual-beam optical trap will be built for these experiments. The trap will be used to bend individual MTs, by exerting force on beads bound to each end of the MT. Included in the trap design is the ability to accurately measure applied force. Knowing the applied force and resultant curve in the MT will enable the determination of the MT stiffness. These measurements will be carried out in the absence and presence of MAPs, so that their effect on stiffness can be measured. Phosphorylated and genetically engineered MAPs will also be used in these studies, to examine their relative effects.
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