Tau's Proline Rich Region Dominates Tubulin Binding

Abstract

Tau is an intrinsically disordered, microtubule associated protein best known for its role neurodegenerative tauopathies such as Alzheimer's disease. Tau's physiological roles include stabilizing microtubules and regulating microtubule dynamic instability. Considerable attention has been given to tau's microtubule binding region (MTBR), and more recently to its MTBR-flanking R’ region, and their role in tau binding to both microtubules and soluble tubulin. N-terminally flanking the MTBR is the proline rich region (PRR), which is widely accepted as critical for tau-mediated polymerization of microtubules and also cited as demonstrating weak microtubule binding. Here, we investigate the role of the PRR in tau binding to soluble tubulin. We find that the PRR dominates binding of tau to soluble tubulin. The PRR has two equivalent binding sites for soluble tubulin dimers, and surprisingly, competes with the MTBR-R’ for binding to soluble tubulin suggesting at least partial overlap of the binding sites in these separate regions. In the absence of the MTBR, PRR is capable of binding microtubules and polymerizing tubulin, albeit weakly. Collectively, our data suggests the PRR region is an important binding motif for the soluble tubulin pool. Interestingly, this domain is not visible in the recent cryo-EM structure of microtubule-bound tau. Future work will focus on describing the relationship between PRR and MTBR-R’ on the microtubule.