Order from Disorder: The Intrinsically Disordered Protein Tau Facilitates Higher-Order Assembly of Microtubules

Abstract

Neurofibrillary tangles, the hallmark intracellular symptom of Alzheimer's disease, are aggregations of hyperphosphorylated tau. In its non-diseased state, the microtubule-associated protein tau, a neuronal polyampholyte, promotes assembly of microtubules and serves other critical cell functions. However, characterizing both diseased and non-diseased states have been difficult. Tau is an intrinsically disordered protein, precluding protein crystallography of its structure. Even studying the effects of tau on microtubules is complicated due to the dynamic instability, the cyclic growth and depolymerization of microtubules. While the drug taxol is often used to stabilize microtubules, there is burgeoning evidence that taxol affects microtubule structure and assembly (M.C. Choi et al., BioPhys J., 2009, 97, 519-527).Solution x-ray diffraction, optical microscopy, and EM were used to study the structure of microtubule/tau mixtures near physiological conditions. Surprisingly, in the presence of tau, the microtubules organized into an open bundled structure with a large microtubule-wall-to-wall spacing (approximately 20 to 40 nm), much larger than expected from polyampholyte theory. The bundle lattice parameter was modulated by differences in the projection domain, a little understood segment of tau that gives rise to the different N-termini of tau isoforms. To understand the functional structure of tau, constructs with deleted domains were created to see how specific regions (or lack thereof) affected the packing behavior of the microtubules. It was determined that certain regions of tau are not necessary for bundling (in conflict with existing models), but their presence might give insight into tau's physiological role in the neuron and how it might evolve into its diseased state.