Towards a Model of the Tau-Tubulin Complex

Abstract

Tau is a microtubule-associated protein which functions to maintain microtubule stability as well as promote microtubule polymerization in the axons of neurons. Its self-association and deposition as neurofibrillary tangles is also one of the primary pathological features of Alzheimer's disease and a broad array of other neurodegenerative disorders. We previously showed that altered interactions between tau and tubulin heterodimers are associated with impaired microtubule polymerization and that the interaction between tau and soluble tubulin may play an important role in both tau function and dysfunction. However, a detailed description of the tau-tubulin complex is lacking. This is in part due to the challenges associated with characterizing this complex, in particular the highly dynamic character of the intrinsically disordered tau as well its ability to accelerate tubulin polymerization. Here, we studied the interaction between tau and tubulin heterodimers using fluorescence correlation spectroscopy (FCS) and acrylodan fluorescence which allow us to propose a detailed model of the complex. Our results provide insight into differential roles of the individual microtubule binding repeats in mediating the tau-tubulin interaction and further illuminate the mechanism by which tau promotes tubulin polymerization.