Intrinsically Disordered Map Tau Mediates both Short-Range Attraction and Long-Range Repulsion between Microtubules

Neurofibrilliary tangles, the hallmark intracellular symptom of Alzheimer's disease, are the aggregated form of hyperphosphorylated tau. To give insight on the diseased state, the complete understanding of the healthy, physiological function of tau is necessary but difficult due to the intrinsically disordered nature of the protein. All isoforms of tau are often found bound to microtubule surfaces, but the N-terminal tail (with isoform-dependent lengths) is thought to project off the microtubule surface and interact with the N-terminal tail of tau proteins on other microtubule surfaces. The forces effected by tau-coated microtubules in the physiological composition range were investigated using small-angle X-ray scattering (SAXS). Samples were osmotically stressed using depletants to replicate the packed axoplasmic environment in which tau and microtubules are found. In going from no coverage of tau to high coverage (1:10 tau-to-tubulin molar ratio, near the physiological limit) isoforms with longer N-terminal tails sterically stabilized microtubules, preventing bundling up to ≈10,000 Pa (in comparison to microtubule bundling at ≈1,000 Pa in absence of tau). In striking contrast, coverage by tau isoforms with the shortest N-terminal tails did not change the bundling pressure (≈1,000 Pa), even at high coverages (1:10 tau-to-tubulin molar ratio). Surprisingly, in the high-pressure limit, the polyampholytic nature of tau brought about a coverage-dependent and irreversible electrostatic attraction between microtubules. The unique manifestation of both short-range electrostatic attraction and long-range steric repulsion by tau on microtubules gives insight to both the physiological function of tau and the design of biologically-inspired materials with multiple interaction motifs.