Near-atomic model of microtubule-tau interactions

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Science  15 Jun 2018:
Vol. 360, Issue 6394, pp. 1242-1246
DOI: 10.1126/science.aat1780

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Tackling microtubule-tau interactions

Alzheimer's disease is a major cause of death in the elderly. Disease progression is associated with the accumulation of neurofibrillary tangles composed of tau, a protein important for neuronal development and function. Tangle formation is preceded by phosphorylation events that cause tau to dissociate from its native binding partner, microtubules. Microtubule-tau interactions have been mysterious. Kellogg et al. used cryo–electron microscopy and molecular modeling to show how tau interacts with the outer surface of the microtubule, stapling together tubulin subunits and thus stabilizing the polymer. A key tau amino acid within the tightly bound segment between tubulin subunits corresponds to a clinically relevant site of tau phosphorylation, explaining the competition between microtubule interaction and tau aggregation.

Science, this issue p. 1242


Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer’s disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo–electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces.

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