An N-terminal motif unique to primate tau enables differential protein-protein interactions.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Cerebral Cortex, Computational Biology, Conserved Sequence, Gene Deletion, Gene Ontology, HEK293 Cells, Humans, Immunoprecipitation, Mice, Knockout, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Neurons, Peptide Fragments, Primates, Protein Interaction Domains and Motifs, Protein Multimerization, Recombinant Fusion Proteins, Sequence Alignment, tau Proteins
Amino Acid Sequence, Animals, Cerebral Cortex, Computational Biology, Conserved Sequence, Gene Deletion, Gene Ontology, HEK293 Cells, Humans, Immunoprecipitation, Mice, Knockout, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Neurons, Peptide Fragments, Primates, Protein Interaction Domains and Motifs, Protein Multimerization, Recombinant Fusion Proteins, Sequence Alignment, tau Proteins
J Biol Chem
Date: Dec. 09, 2017
PubMed ID: 29382714
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