Abstract
During neuronal development, the microtubule-associated protein tau becomes enriched in the axon, where it remains concentrated in the healthy brain. In tauopathies such as Alzheimer's disease, tau redistributes from the axon to the somatodendritic compartment. However, the cellular mechanism that regulates tau's localization remains unclear. We report here that tau interacts with the Ca2+-regulated plasma membrane-binding protein annexin A2 (AnxA2) via tau's extreme N terminus encoded by the first exon (E1). Bioinformatics analysis identified two conserved eight-amino-acids-long motifs within E1 in mammals. Using a heterologous yeast system, we found that disease-related mutations and pseudophosphorylation of Tyr-18, located within E1 but outside of the two conserved regions, do not influence tau's interaction with AnxA2. We further observed that tau interacts with the core domain of AnxA2 in a Ca2+-induced open conformation and interacts also with AnxA6. Moreover, lack of E1 moderately increased tau's association rate to microtubules, consistent with the supposition that the presence of the tau-annexin interaction reduces the availability of tau to interact with microtubules. Of note, intracellular competition through overexpression of E1-containing constructs reduced tau's axonal enrichment in primary neurons. Our results suggest that the E1-mediated tau-annexin interaction contributes to the enrichment of tau in the axon and is involved in its redistribution in pathological conditions.
Highlights
During neuronal development, the microtubule-associated protein tau becomes enriched in the axon, where it remains concentrated in the healthy brain
Because we have shown that tau binds to the core domain of annexin A2 (AnxA2), it might interact with other members of the annexin family
We have previously shown that the neuronal microtubuleassociated protein tau interacts with the calcium-regulated plasma membrane-binding protein AnxA2; the interaction sites of both proteins and potential functional consequences remained unknown
Summary
We have identified the calcium-regulated plasma membrane– binding protein AnxA2 as an interaction partner of tau by tandem-affinity purification tag purification and MS [17]. After neuronal differentiation of transfected PC12 cells, PAGFP was activated within a segment in the middle of the process by a laser flash at 407-nm wavelength, and FDAP was recorded in the activated region as a function of time Both constructs showed a much slower decay than a non-MT-binding control protein of similar size (3ϫPAGFP), indicating binding to microtubules (Fig. 4B). After expression of the competing constructs coding for E1 or for E1 and the amino acid sequence of exon 2 (E2), most of the infected neurons lost the preferential staining of endogenous tau in the axon, and the tau signal was present in multiple processes (Fig. 5A, middle and bottom). Quantification confirmed that overexpression of the competing constructs abolishes the preferential distribution of endogenous tau in one process (Fig. 5A, right; F(2,9) ϭ 179.3, p Ͻ 0.001), suggesting that tau’s interaction via its first coding exon contributes to its enrichment in the axon. We observed axonal exclusion of MAP2 in the vast majority of neurons after expression of the control construct (3ϫmCherry), which did not change with constructs containing E1, suggesting that overexpression of E1 affected the distribution of tau
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