An N-terminal motif unique to primate tau enables differential protein–protein interactions

Kristie Stefanoska, Alexander Volkerling, Josefine Bertz, Anne Poljak, Yazi D. Ke, Lars M. Ittner, Arne Ittner

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38 Citations (Scopus)
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Compared with other mammalian species, humans are particularly susceptible to tau-mediated neurodegenerative disorders. Differential interactions of the tau protein with other proteins are critical for mediating tau’s physiological functions as well as tau-associated pathological processes. Primate tau harbors an 11-amino acid-long motif in its N-terminal region (residues 18 –28), which is not present in non-primate species and whose function is unknown. Here, we used deletion mutagenesis to remove this sequence region from the longest human tau isoform, followed by glutathione S-transferase (GST) pulldown assays paired with isobaric tags for relative and absolute quantitation (iTRAQ) multiplex labeling, a quantitative method to measure protein abundance by mass spectrometry. Using this method, we found that the primate-specific N-terminal tau motif differentially mediates interactions with neuronal proteins. Among these binding partners are proteins involved in synaptic transmission (synapsin-1 and synaptotagmin-1) and signaling proteins of the 14-3-3 family. Furthermore, we identified an interaction of tau with a member of the annexin family (annexin A5) that was linked to the 11-residue motif. These results suggest that primate Tau has evolved specific residues that differentially regulate protein–protein interactions compared with tau proteins from other non-primate mammalian species. Our findings provide in vitro insights into tau’s interactions with other proteins that may be relevant to human disease.

Original languageEnglish
Pages (from-to)3710-3719
Number of pages10
JournalJournal of Biological Chemistry
Issue number10
Publication statusPublished - 11 Mar 2018
Externally publishedYes


  • Tau protein (Tau)
  • Tauopathy
  • Neurochemistry
  • Mass spectrometry (MS)
  • Protein-protein interaction


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