The microtubule-associated protein tau is an unstructured protein found in neuronal axons. It binds to microtubules (MTs) and regulates their dynamics and is known to stabilize microtubules against depolymerization in neuronal axons, ensuring proper trafficking of organelles along microtubules in long axons. Abnormal interactions between Tau and microtubules are implicated in Alzheimer’s disease and other neurodegenerative disorders. There are six tau isoforms, having three or four MT binding domains, with either short, medium or long projection N-terminal tails (NTTs) domains. Direct force measurement between taxol-stabilized MTs coated with distinct Tau isoforms showed that isoforms with longer NTTs sterically stabilized MTs compared with bare MTs or with MTs that were coated with short NTTs.

The tau isofroms with longer NTTs can undergo mushroom to brush transition with increasing tau coverage. This gain of function by longer isoforms in imparting steric stabilization to microtubules is essential in preventing microtubule aggregation and loss of function in organelle trafficking. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment (PNAS 2015).