Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau's interaction with microtubules in axon-like processes

Mol Biol Cell. 2016 Nov 7;27(22):3537-3549. doi: 10.1091/mbc.E16-06-0402. Epub 2016 Aug 31.


A current challenge of cell biology is to investigate molecular interactions in subcellular compartments of living cells to overcome the artificial character of in vitro studies. To dissect the interaction of the neuronal microtubule (MT)-associated protein tau with MTs in axon-like processes, we used a refined fluorescence decay after photoactivation approach and single-molecule tracking. We found that isoform variation had only a minor influence on the tau-MT interaction, whereas the presence of a C-terminal pseudorepeat region (PRR) greatly increased MT binding by a greater-than-sixfold reduction of the dissociation rate. Bioinformatic analysis revealed that the PRR contained a highly conserved motif of 18 amino acids. Disease-associated tau mutations in the PRR (K369I, G389R) did not influence apparent MT binding but increased its dynamicity. Simulation of disease-like tau hyperphosphorylation dramatically diminished the tau-MT interaction by a greater-than-fivefold decrease of the association rate with no major change in the dissociation rate. Apparent binding of tau to MTs was similar in axons and dendrites but more sensitive to increased phosphorylation in axons. Our data indicate that under the conditions of high MT density that prevail in the axon, tau's MT binding and localization are crucially affected by the presence of the PRR and tau hyperphosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Axons / metabolism
  • Cell Culture Techniques
  • Computational Biology
  • Conserved Sequence
  • Humans
  • Microtubules / metabolism
  • Microtubules / physiology
  • Neurons
  • Optical Imaging / methods
  • PC12 Cells
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Protein Isoforms / metabolism
  • Rats
  • tau Proteins / genetics
  • tau Proteins / metabolism*
  • tau Proteins / physiology


  • Protein Isoforms
  • tau Proteins