Tau avoids the GTP cap at growing microtubule plus ends

Plus-end tracking proteins (+TIPs) are a group of proteins that associate with the growing end of microtubules and mediate important cellular functions including neural development and cell division. Work in recent years has shown that the majority of +TIPs are directed to the plus-end through a family of end binding proteins (EBs), which preferentially bind the stabilizing cap of GTP-tubulin present during microtubule growth, versus weaker binding to GDP-tubulin in the proximal microtubule. One question yet to be addressed is whether there may exist other microtubule associated proteins (MAPs) that preferentially bind specific nucleotide states of tubulin. Here we report that the neuronal MAP tau, which is enriched in axons where it promotes microtubule growth and bundling, preferentially binds GDP-tubulin (KD = 0.26 {micro}M) over GMPCPP-tubulin (KD = 1.1 {micro}M) in vitro as well as GTP-tubulin at the tips of growing microtubules in vitro and in vivo. This nucleotide preference causes tau binding to lag behind the growing microtubule plus-end by about 100-200 nm both in vitro and in live cells. Thus, tau is a microtubule tip avoiding protein, establishing a new class of tip avoiding MAPs, and acts primarily by suppressing microtubule shortening rather than promoting growth. We speculate that neurological disease-relevant tau mutations may exert their phenotype by their failure to properly recognize GDP-tubulin, thus displacing +TIPs, such as EB3, and their associated activities into abnormal locations in the neuron.