Determining a Topological Model for TAU Bound to Tubulin Heterodimers

Tau is an intrinsically disordered neuronal protein whose aggregation and deposition as neurofibrillary tangles is a hallmark of several tauopathies, including Alzheimer's disease. It is thought that the loss of native interaction between tau and microtubules (MTs) also contributes for pathology. Despite intense study, structural details of the tau-tubulin complex are lacking, in part due to its highly dynamic nature and the capacity of tau to promote tubulin polymerization. To overcome these limitations, we use single-molecule Forster Resonance Energy Transfer (smFRET) to observe conformational changes in tau upon binding to tubulin. Our results show that overall tau adopts an extended conformation upon binding, in which the long-range of contacts between both termini and the microtubule binding region (MTBR) that characterize its compact solution structure are lost. More importantly, in contrast with its aggregation-prone structure,1 the MTBR become more extended in the tau-tubulin complex, although this extension is not evenly distributed through all four repeat domains. Comparison of tau isoforms containing or lacking repeat 2 suggest conformational differences that may relate to differences in affinity and function of these two isoforms. Notably, our results unequivocally support a model of tau with distinct ensemble conformations upon interaction with soluble tubulin and polyanions that promote its aggregation. This work provides insight into conformational changes important to tau loss of function and draws attention to the importance of the role of tau's conformational plasticity in this process.1. Elbaum-Garfinkle S and Rhoades E (2012) J Am Chem Soc 134(40):16607–16613