Increased Affinity for Tubulin Impairs Tau Function

Tau is a microtubule binding protein that forms pathological aggregates in the brain in Alzheimer's disease and other tauopathies. Disease etiology is thought to arise from loss of native interactions between tau and microtubules, as well as from gain of toxicity tied to tau aggregation, although neither mechanism is well-understood. We have investigated the link between function and disease using disease-associated and designed disease-motivated mutants of tau. We used fluorescence correlation spectroscopy (FCS) to measure tau binding to free tubulin. We find that while the mutants bind stabilized microtubules with comparable affinities, they demonstrate an increased affinity for tubulin dimers. Morover, the mutant forms of tau are impaired in their ability to promote microtubule assembly. Using single molecule FRET, we measure conformational changes in tau upon binding to tubulin that provide a structural framework for the observed altered affinity and function. We propose a model that describes tau binding to tubulin dimers and a mechanism by which disease-relevant alterations to tau impact its function. Together, these results draw attention to the relevance of the interaction between tau and free tubulin as playing an important role in mechanisms of tau pathology.View Large Image | View Hi-Res Image | Download PowerPoint Slide